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Harefuah.
2006 Dec;145(12):889-94, 942. |
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[Clinical, biochemical and molecular
characterization of rare genetic disorders, related to nucleotide excision
repair (NER) system]
[Article
in Hebrew]
Falik-Zaccai T,
Kfir N, Laskar M, Segel R, Khyat M, Slor H.
Institute
of Human Genetics, Western Galilee Hospital, Naharia, Israel. tzipora.falik@naharia.health.gov.il
All
living organisms are equipped with DNA repair systems that can cope with a wide
variety of DNA lesions. Among these repair pathways, nucleotide excision repair
(NER) is quite versatile, involved in the removal of a variety of bulky DNA
lesions induced by ultraviolet light and chemical carcinogens and mutagens. The
importance of NER for human health is illustrated mainly by the occurrence of
rare life-threatening disorders such as Xeroderma Pigmentosum (XP), Cockayne
Syndrome (CS) and Trichthiodystrophy (TTD). XP, CS and most TTD patients
exhibit increased sensitivity to UV light and premature aging. XP is associated
with a high incidence of skin tumors, CS is primarily a developmental disorder
associated with failure to thrive, and psychomotor retardation. The authors
report the clinical, biochemical and molecular aspects of the NER pathway in
individuals suspected to have a DNA repair, NER type-related disease. These
diseases are rare worldwide, but are frequent in Israel, probably due to the
high rate of consanguinity among certain Arab, Druze and Jewish populations.
Our laboratory is the only one in Israel, and one of very few labs world-wide
that is performing DNA repair evaluation as a diagnostic test for DNA
repair-deficient inherited diseases. Identification of the causative genes and
proteins in suspected families will facilitate accurate diagnosis, genetic
counseling, identification of couples at risk and prenatal
diagnosis.
Publication Types:
English Abstract
PMID: 17220027
[PubMed - in process]
|
Nature.
2006 Dec 21;444(7122):1015-7. |
Nature. 2006 Dec
21;444(7122):1038-43.
Ageing: too fast by mistake.
Kirkwood T.
Publication
Types:
Comment
News
PMID: 17183304
[PubMed - indexed for MEDLINE]
|
Gynecol
Oncol. 2006 Dec;103(3):891-6. Epub 2006 Jun 23. |
Nucleotide excision repair genotype and the
incidence of endometrial cancer: effect of other risk factors on the
association.
Weiss JM, Weiss NS, Ulrich CM, Doherty JA, Chen C.
Program
in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer
Research Center, Department of Epidemiology, School of Public Health and
Community Medicine, University of Washington, Seattle, WA, USA.
weissjoc@mail.nih.gov
OBJECTIVES: Certain nucleotide excision
repair (NER) genotypes appear to be associated with an altered risk of
endometrial cancer. These associations could be modified by characteristics and
exposures that themselves influence risk of disease. METHODS: We conducted a
population-based case-control study in western Washington State to address the
role of specific NER genotypes in conjunction with relevant exposures, such as
postmenopausal hormone therapy, obesity, parity, oral contraceptive use, and
cigarette smoking on risk of endometrial cancer. Case women (n=371), ages 50-69
years, were diagnosed with invasive endometrial cancer between 1994 and 1999.
Control women (n=420), matched to cases on age and county of residence, were selected
using random-digit dialing (ages 50-65) and random selection from HCFA data
files (ages 66-69). RESULTS: Risk of endometrial cancer was not associated with
ERCC1, ERCC2 (XPD), ERCC4 (XPF), or ERCC5 (XPG) genotype. A reduced risk of
endometrial cancer was observed with presence of the XPA g23a variant allele,
but only among women with a history of oral contraceptive use (OR 0.47, 95% CI
0.32-0.69). A decreased risk associated with carriage of at least one variant
allele for both XPC A499V and XPC K939Q was restricted to women with BMI<30
kg/m2 (OR 0.45, 95% CI 0.25-0.82). The size of the association between these
genotypes and risk of endometrial cancer did not differ by postmenopausal
hormone use, parity, or smoking. CONCLUSIONS: Our study provides limited
evidence for interactions between NER genotypes and DNA damage-causing
exposures in the etiology of endometrial cancer. Subsequent studies are needed
to confirm the observed associations.
Publication Types:
Research Support,
N.I.H., Extramural
Research Support,
Non-U.S. Gov't
PMID:
16806437 [PubMed - indexed for MEDLINE]
|
Breast
Cancer Res Treat. 2006 Jan;95(1):73-80. Epub 2005 Dec 1. |
Polymorphisms of the DNA repair genes XPD
(Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp): relationship to breast cancer
risk and familial predisposition to breast cancer.
Brewster AM, Jorgensen TJ, Ruczinski I, Huang HY, Hoffman S, Thuita L, Newschaffer C, Lunn RM, Bell D, Helzlsouer KJ.
Department
of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center,
Houston, TX 77230-1439, USA. abrewster@mdanderson.org
Family
history is a risk factor for breast cancer and could be due to shared
environmental factors or polymorphisms of cancer susceptibility genes.
Deficient function of DNA repair enzymes may partially explain familial risk as
polymorphisms of DNA repair genes have been associated, although
inconsistently, with breast cancer. This population based case-control study
examined the association between polymorphisms in XPD (Lys751Gln) and XRCC1
(Arg399Gln and Arg194Trp) genes, and breast cancer. Breast cancer cases (n=321)
and controls (n=321) were matched on age and menopausal status. Conditional
logistic regression was used to estimate odds ratios (OR) and 95% confidence
intervals (CI). The analysis was conducted omitting observations with missing
data, and by using imputation methods to handle missing data. No significant
association was observed between the XPD 751Gln/Lys (OR 1.37, 95% CI 0.96-1.96)
and Gln/Gln genotypes (OR 1.08, 95% CI 0.62-1.86) (referent Lys/Lys), XRCC1
399Arg/Gln (OR 1.48, 95% CI 0.92-2.38) and Gln/Gln genotypes (1.11, 95% CI
0.67-1.83) (referent Arg/Arg) or the XRCC1 Arg/Trp and Trp/Trp genotypes (OR
1.12, 95% CI 0.69-1.83) (referent Arg/Arg) and breast cancer. In multivariate
analysis, the adjusted odds ratios for the XPD and XRCC1 399 polymorphisms
increased and became statistically significant, however, were attenuated when
imputation methods were used to handle missing data. There was no interaction
with family history. These results indicate that these polymorphisms in XPD and
XRCC1 genes are only weakly associated with breast cancer. Without imputation
methods for handling missing data, a statistically significant association was
observed between the genotypes and breast cancer, illustrating the potential
for bias in studies that inadequately handle missing
data.
Publication Types:
Comparative Study
Research Support,
N.I.H., Extramural
Research Support,
Non-U.S. Gov't
PMID:
16319991 [PubMed - indexed for MEDLINE
|
J
Dermatolog Treat. 2006;17(4):241-3. |
Xeroderma pigmentosum and lentigo maligna in
identical twins.
Faghihi G, Radan M.
Department
of Dermatology, Shahid Beheshti Hospital, Isfahan University School of
Medicine, Isfahan, Iran.
Xeroderma pigmen tosum (XP) is a rare
autosomal recessive genodermatosis. Skin abnormalities result from an inability
to repair UV-damaged DNA. Clinically, XP presents with early onset cutaneous
changes (severe photosensitivity, actinic keratoses, and telangiectasias) and
an increase of developing cutaneous malignancies beginning in early childhood,
but lentigo maligna and melanomas are relatively rare. Here we report on
homozygote twins in whom there was no positive family history. They showed
subnormal physical growth. On ophthalmological examination, both had
photophobia and decreased visual acuity. Since birth, several excisions had
been performed for skin neoplasms. In one of them a pigmented patch developed
over the frontal area which proved to be lentigo maligna and she was referred
to a dermato-oncology center. They have been given isotretinoin and physical
sunscreen since then. The follow-up period was extended to 2 years and no
serious complications occurred from the above treatment. This is an interesting
report about XP in twins with the presentation of the rare neoplasm lentigo
maligna.
PMID: 16971321 [PubMed - in process]
|
Ai
Zheng. 2006 Sep;25(9):1113-9. |
[Correlation of XPC Ala499Val and Lys939Gln
Polymorphisms to Risks of Esophageal Squamous Cell Carcinoma and Gastric
Cardiac Adenocarcinoma.]
[Article in Chinese]
Zhou RM, Li Y, Wang N, Zhang XJ, Dong XJ, Guo W.
Laboratory
of Molecular Biology, Hebei Provincial Cancer Institute, Shijiazhuang, Hebei,
050011,P. R. China.guoweiz2002@yahoo.com.cn.
BACKGROUND &
OBJECTIVE: Xeroderma pigmentosum group C(XPC) gene is involved in nucleotide
excision repair (NER). Single nucleotide polymorphisms (SNP) in XPC gene may
affect DNA repairing capacity and genetic susceptibility to cancer. This study
was to investigate the correlation of XPC exon 8 Ala499Val and exon 15
Lys939Gln SNPs to the susceptibility of esophageal squamous cell carcinoma
(ESCC) and gastric cardiac adenocarcinoma (GCA) in a population at a high
incidence region of Hebei Province. METHODS: XPC exon 8 Ala499Val and exon 15
Lys939Gln SNPs were genotyped by polymerase chain reaction-restrictive fragment
length polymorphism (PCR-RFLP) analysis in 327 ESCC patients, 253 GCA patients,
and 612 healthy controls. RESULTS: The number of the subjects with family
history of upper gastrointestinal cancer (UGIC) was significantly higher in
ESCC and GCA groups than in control group. Family history of UGIC may increase
the risk of developing ESCC and GCA [age and gender adjusted odds ratio (OR)
=1.76 and 1.77, 95% confidence interval (CI) = 1.34-2.32 and 1.31-2.39]. The
overall allelotype and genotype distributions of XPC exon 8 Ala499Val in ESCC
patients were not significantly different from those in healthy controls
(P>0.05). T allelotype frequence of XPC exon 8 in GCA patients was 26.5%,
which was significantly lower than that in healthy controls (Chi2=6.12, P=0.01).
The C/T genotype frequencies of XPC exon 8 in GCA patients and healthy controls
were 35.6% and 46.1% respectively. Compared with individuals with C/C genotype,
individuals with C/T genotype had significantly lower risk in developing GCA
(OR=0.62, 95% CI=0.45-0.84). When stratified for smoking status and family
history of UGIC, compared with individuals with C/C genotype, individuals with
C/T genotype in smoker group and in the group without family history of UGIC
had lower risk in developing GCA (OR=0.57, 95% CI=0.36-0.91 and 0.37-0.88). The
overall allelotype and genotype distributions of XPC exon 15 Lys939Gln in ESCC
and GCA patients were not significantly different from those in healthy
controls (P>0.05). When stratified for smoking status and family history of
UGIC, compared with individuals with A/A genotype, individuals in non-smoker
group with C/C genotype had higher risk in developing ESCC (OR=2.05, 95%
CI=1.15-3.66). The haplotype distribution of ESCC patients was not
significantly different from that of healthy controls (P>0.05), while the
haplotype distribution of GCA patients was significantly different from that of
healthy controls (P=0.02). Compared with A/T haplotype, A/C and C/C haplotypes
significantly increased the risk of developing GCA (OR=1.35 and 1.46, 95%
CI=1.01-1.81 and 1.06-2.00). CONCLUSIONS: In the high incidence region of Hebei
Province, C/T genotype of XPC exon 8 may decrease the risk of developing GCA.
Lys939Gln SNP in exon 15 may have no influence on the risk of ESCC and GCA, but
when stratified for smoking status, C/C genotype of XPC exon 15 may increase
the risk of developing ESCC in non-smoking population. While A/C and C/C
haplotypes may increase the risk of developing GCA.
PMID: 16965652
[PubMed - in process]
|
Mutat
Res. 2006 Sep 7; [Epub ahead of print] |
Role of nucleotide excision repair deficiency in
intestinal tumorigenesis in multiple intestinal neoplasia (Min)
mice.
Steffensen IL, Schut HA, Nesland JM, Tanaka K, Alexander J.
Department
of Food Toxicology, Division of Environmental Medicine, Norwegian Institute of
Public Health, NO-0403 Oslo, Norway.
Mice deficient in the
Xeroderma pigmentosum group A (Xpa) gene are defective in nucleotide excision
repair (NER) and highly susceptible to skin carcinogenesis after dermal
exposure to UV light or chemicals. Min (multiple intestinal neoplasia) mice,
heterozygous for a germline nonsense mutation in the tumor suppressor gene
adenomatous polyposis coli (Apc), develop intestinal tumors spontaneously and
show additional intestinal tumors after exposure to the food mutagen
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In this study, we
investigated the impact of loss of XPA function on PhIP-induced intestinal
tumorigenesis in F1 offspring of Min/+ (Apc(+/-)) mice crossed with Xpa
gene-deficient mice. Apc(+/-) mice lacking both alleles of Xpa had higher
susceptibility towards toxicity of PhIP, higher levels of PhIP-DNA adducts in
the middle and distal small intestines as well as in liver, and a higher number
of small intestinal tumors at 11 weeks, compared with Apc(+/-) mice with one or
two intact Xpa alleles. Localization of tumors was not affected, being highest
in middle and distal small intestines in all genotypes. At 11 weeks of age, the
number of spontaneous intestinal tumors was not significantly increased by
homozygous loss of Xpa, but untreated Apc(+/-)/Xpa(-/-) mice had significantly
shorter life-spans than their XPA-proficient littermates. Heterozygous loss of
Xpa did not affect any of the measured end points. In conclusion, the Xpa gene
and the NER pathway are involved in repair of bulky PhIP-DNA adducts in the
intestines and the liver, and most probably of DNA lesions leading to
spontaneous intestinal tumors. These results confirm a role of the NER pathway
also in protection against cancer in internal organs, additional to its
well-known importance in protection against skin cancer. An effect of Apc(+/-)
on adduct levels, additional to that of Xpa(-/-), indicates that the truncated
APC protein may affect a repair pathway other than NER.
PMID:
16962818 [PubMed - as supplied by publisher]
|
Mutat
Res. 2006 Jul 25;599(1-2):124-34. Epub 2006 Mar 27. |
Polymorphisms in DNA repair genes as risk factors
for asbestos-related malignant mesothelioma in a general population
study.
Dianzani I, Gibello L, Biava A, Giordano M, Bertolotti M, Betti M, Ferrante D, Guarrera S, Betta GP, Mirabelli D, Matullo G, Magnani C.
Laboratorio
di Patologia Genetica, Dipartimento di Scienze Mediche, Universita del Piemonte
Orientale, Via Solaroli 17, 28100 Novara, Italy.
irma.dianzani@med.unipmn.it
Differences in response to
carcinogenic agents are due to the allelic variants of the genes that control
it. Key genes are those involved in the repair of the DNA damage caused by such
agents. This paper describes the results of a case-control epidemiological
study designed to determine the genotypes of four of these genes in persons
exposed to a single genotoxic factor, i.e. asbestos, who had or had not
developed malignant mesothelioma (MM). Our working hypothesis was that an
imperfect DNA repair, as revealed by subtle polymorphic variants, could reduce
protection against the chronic DNA insult provoked by asbestos and eventually
result in mutagenesis and cancer. Seven variants (i.e. XRCC1-R399Q-NCBI SNP,
XRCC1-R194W, XRCC3-T241M, XRCC3-IVS6-14, XPD-K751Q, XPD-D312N, OGG1-S326C) were
investigated in 81 patients and 110 age and sex-matched controls, all residents
at Casale Monferrato, a Piedmontese town highly exposed to asbestos pollution.
Unconditional multivariable logistic regression was used to estimate odds
ratios (ORs) and 95% confidence intervals (CIs). When considered as a
categorical variable, XRCC1-399Q showed an increased OR both in heterozygotes
(OR=2.08; 95% CI=1.00-4.33) and homozygotes (2.38; 95% CI=0.82-6.94), although
individual ORs were not significant. When it was considered as a continuous
variable OR was significant (OR=1.68; 95% CI: 1.02-2.75). When genotypes were
divided into "non-risk" and "risk" genotypes, i.e. those
thought to be associated with increased risk in the light of the functional
significance of the variants, XRCC1-399Q (Q homozygotes+Q/R heterozygotes
versus R homozygotes) had an OR=2.147 (95% CI: 1.08-4.28), whereas that of
XRCC3-241T (T homozygotes+M/T heterozygotes versus M homozygotes) was 4.09 (95%
CI: 1.26-13.21) and that of OGG1-326C was increased, though not significantly.
None of the haplotypes showed a significantly different frequency between
patients and controls. This is the first report of an association between
polymorphisms in DNA repair genes and asbestos-associated MM. Our data indicate
that genetic factors are involved in MM development.
PMID:
16564556 [PubMed - indexed for MEDLINE]
|
Br
J Dermatol. 2006 Jul;155(1):81-8. |
A novel
mutation in the XPA gene associated with unusually mild clinical features in a
patient who developed a spindle cell melanoma.
Sidwell RU, Sandison A, Wing J, Fawcett HD, Seet JE, Fisher C, Nardo T, Stefanini M, Lehmann AR, Cream JJ.
Histopathology,
Charing Cross Hospital, London, U.K.
Background Xeroderma
pigmentosum (XP) is an autosomal recessive disorder of, in most cases,
defective nucleotide excision repair (NER) of ultraviolet radiation (UV)- and
chemical-induced DNA damage. The condition is characterized by an increased
sensitivity of the skin to UV radiation, with early development of pigmentary
changes and premalignant lesions in sun-exposed areas of the skin, signs of
photoageing and a greatly increased incidence from a young age of skin tumours
including melanoma. Approximately 20% of patients with XP show neurological
abnormalities of varying severity due to primary neuronal degeneration. Genetic
analysis by somatic cell hybridization has led to the identification in the NER-defective
form of XP of seven complementation groups, designated XP-A to XP-G. These
complementation groups correspond to different proteins involved in the NER
process. XP-A classically includes some of the most severely affected patients.
Objectives We describe a 61-year-old Punjabi woman with XP. Remarkably she had
only mild cutaneous abnormalities, minimal neurological features and unusual
longevity, and developed a malignant spindle cell melanoma. There are few
previous reports of spindle cell melanoma associated with XP. To gain insight
into the aetiology of these unusual features, we sought to analyse the DNA
repair properties of the patient and identify the complementation group and the
causative mutation in the defective gene. Methods Unscheduled DNA synthesis and
the inhibition of RNA synthesis were measured. The complementation group was
assigned by fusing the cells of our patient with XP cells of known
complementation groups and determining the ability to carry out unscheduled DNA
repair. Molecular analysis of the cDNA was carried out by polymerase chain
reaction and DNA sequencing. Results Levels of DNA repair were extremely low
and complementation analysis assigned the defect to the XP-A group. Sequencing
of the XPA gene revealed a novel homozygous mutation of A-->G at the eighth
nucleotide of intron 4 causing aberrant splicing and a nonfunctional truncated
XP-A protein. However, a small amount of normally spliced mRNA was detected at
<5% the level in normal cells. Conclusions The small amount of normally
spliced mRNA detected may be sufficient to explain the relatively mild clinical
features in our patient.
PMID: 16792756 [PubMed - in process]
|
Mutat Res. 2006
Jun 10; [Epub ahead of print] |
Tissue specific
mutagenic and carcinogenic responses in NER defective mouse
models.
Wijnhoven SW, Hoogervorst EM, de Waard H, van der Horst GT, van Steeg H.
National
Institute of Public Health and the Environment (RIVM), Laboratory of
Toxicology, Pathology and Genetics, PO Box 1, 3720 BA, Bilthoven, The
Netherlands.
Several mouse models with defects in genes encoding
components of the nucleotide excision repair (NER) pathway have been developed.
In NER two different sub-pathways are known, i.e. transcription-coupled repair
(TC-NER) and global-genome repair (GG-NER). A defect in one particular NER
protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER
defects in mice predispose to cancer, both spontaneous as well as UV-induced.
As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum
(XP) syndrome. Defects in TC-NER in humans are associated with Cockayne
syndrome (CS), a disease not linked to tumor development. Mice with TC-NER
defects (Csa and Csb) are - except for the skin - not susceptible to develop
(carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and
ERCC1 have functions outside NER, like transcription initiation and
inter-strand crosslink repair. Deficiencies in these processes in mice lead to
very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP
and CS. In most cases these animals have a (very) short life span, display
segmental progeria, but do not develop tumors. Here we will overview the
available NER-related mouse models and will discuss their phenotypes in terms
of (chemical-induced) tissue-specific tumor development, mutagenesis and
premature aging features.
PMID: 16769089 [PubMed - as supplied by
publisher]
|
Am
J Epidemiol. 2006 May 17; [Epub ahead of print] |
XRCC3 and XPD/ERCC2 Single Nucleotide Polymorphisms
and the Risk of Cancer: A HuGE Review.
Manuguerra M, Saletta F, Karagas MR, Berwick M, Veglia F, Vineis P, Matullo G.
Section
of Epidemiology, ISI Foundation (Institute for Scientific Interchange), Torino,
Italy.
Hundreds of polymorphisms in DNA repair genes have been
identified; however, for many of these polymorphisms, the impact on repair
phenotype and cancer susceptibility remains uncertain. In this review, the
authors focused on the x-ray repair cross-complementing protein group 3 (XRCC3)
and xeroderma pigmentosum group D (XPD)/excision repair cross-complementing
rodent repair deficiency (ERCC2) genes, because they are among the most
extensively studied but no final conclusion has yet been drawn about their role
in cancer occurrence. XRCC3 participates in DNA double-strand
break/recombinational repair through homologous recombination to maintain
chromosome stability. XPD/ERCC2 is a helicase involved in the nucleotide
excision repair pathway, which recognizes and repairs many structurally unrelated
lesions, such as bulky adducts and thymidine dimers. The authors identified a
sufficient number of epidemiologic studies on cancer to perform meta-analyses
for XPD/ERCC2 variants in codons 156, 312, and 751 and XRCC3 variants in codon
241. The authors evaluated all cancer sites to investigate whether DNA repair
is likely to take place in a rather nonspecific manner for different
carcinogens and different cancers. For the most part, the authors found no
association between these genes and the cancer sites investigated, except for
some statistically significant associations between XPD/ERCC2 single nucleotide
polymorphisms and skin, breast, and lung cancers.
PMID: 16707649
[PubMed - as supplied by publisher]
|
Cancer.
2006 Apr 28; [Epub ahead of print] |
Xeroderma pigmentosum group D haplotype predicts
for response, survival, and toxicity after platinum-based chemotherapy in
advanced nonsmall cell lung cancer.
Booton R, Ward T, Heighway J, Taylor P, Power F, Ashcroft L, Morris J, Thatcher N.
Christie
Hospital National Health Service Trust, Manchester, United
Kingdom.
BACKGROUND: The treatment of lung cancer has reached a
therapeutic plateau. Several mechanisms of platinum resistance have been
described, including the removal of platinum-DNA adduct by nucleotide excision
repair (NER). Polymorphisms within the Xeroderma pigmentosum Group D protein
(XPD), a member of the NER pathway, are associated with alterations in enzyme
activity and may change sensitivity to platinum-based chemotherapy. The authors
investigated the relation between XPD polymorphisms and treatment response,
toxicity, and overall survival in patients who received platinum-based
chemotherapy for advanced nonsmall cell lung cancer (NSCLC). METHODS: Between
2001 and 2002, 108 patients with chemotherapy-naive, advanced NSCLC were
recruited. Associations between XPD312/751 polymorphisms and XPD haplotype and
treatment response, toxicity. and survival were evaluated. RESULTS: Significant
correlations were observed between XPD haplotype and Grade 4 neutropenia and
overall survival together with a greater response to platinum-based
chemotherapy for the XPD *A haplotype. CONCLUSIONS: The XPD haplotype may
represent a useful pharmacogenomic marker of platinum-based chemotherapy in
patients with advanced NSCLC and requires prospective validation. Cancer 2006.
(c) 2006 American Cancer Society.
PMID: 16649224 [PubMed - as
supplied by publisher]
|
Int
J Cancer. 2006 Apr 27; [Epub ahead of print] |
Genetic
polymorphisms of the XPG and XPD nucleotide excision repair genes in sarcoma
patients.
Le Morvan V, Longy M, Bonaiti-Pellie C, Bui B, Houede N, Coindre JM , Robert J, Pourquier P.
Laboratory
of Pharmacology of Anticancer Agents EA 515, Institut Bergonie & Universite
Victor Segalen Bordeaux 2, Bordeaux, France.
There are more than
50 subtypes of soft tissue sarcomas, among which 30% are associated with
specific genetic alterations, including translocations. Several studies have
reported associations between cancer risk and polymorphisms of DNA repair genes
from the nucleotide excision repair (NER) pathway. NER involves more than 20
proteins whose inactivation leads to xeroderma pigmentosum (XP) or cockayne
syndrome (CS), among which XPD, a helicase allowing DNA strand excision by the
endonuclease XPG. DNA from 93 patients with synovial sarcomas, myxoid
liposarcomas, dermatofibrosarcomas protuberans (DFSP), malignant fibrous
histiocytomas and leiomyosarcomas were genotyped for both XPD Lys751Gln and XPG
Asp1104His polymorphisms. Departure from Hardy-Weinberg was highly significant
for the XPG polymorphism with an excess of heterozygotes in synovial sarcomas
(p = 1.5 x 10(-5)), myxoid liposarcomas (p = 1.5 x 10(-4)) and to a lesser
extent in DFSP (p = 0.028). In the case of XPD, a significant deviation was
observed in synovial sarcomas (p = 3 x 10(-6)) and DFSP (p = 0.0014). When
tumors were pooled according to their genetic alterations, the proportion of
carriers of the variant XPG allele was significantly increased in sarcomas with
specific translocations as compared to sarcomas with complex genetics (p <
10(-9)). No difference was found for XPD. Genotyping of the tumor samples in
synovial sarcomas and myxoid liposarcomas revealed frequent loss of
heterozygosity for XPG, mostly due to the loss of the frequent allele. For XPD,
both alleles were lost with a similar frequency. Our results raise the
potential implication of the XPG Asp1104His polymorphism in the occurrence of
chromosomal translocations associated with specific subtypes of sarcomas. (c)
2006 Wiley-Liss, Inc.
PMID: 16646069 [PubMed - as supplied by
publisher]
|
Mol
Cell. 2006 Apr 7;22(1):27-37. |
Conserved
XPB Core Structure and Motifs for DNA Unwinding: Implications for Pathway
Selection of Transcription or Excision Repair.
Fan L, Arvai AS, Cooper PK, Iwai S, Hanaoka F, Tainer JA.
Life
Sciences Division, Department of Molecular Biology, Lawrence Berkeley National
Laboratory, Berkeley, California 94720; Department of Molecular Biology, Skaggs
Institute of Chemical Biology, The Scripps Research Institute, La Jolla,
California 92037.
The human xeroderma pigmentosum group B (XPB)
helicase is essential for transcription, nucleotide excision repair, and TFIIH
functional assembly. Here, we determined crystal structures of an Archaeoglobus
fulgidus XPB homolog (AfXPB) that characterize two RecA-like XPB helicase
domains and discover a DNA damage recognition domain (DRD), a unique RED motif,
a flexible thumb motif (ThM), and implied conformational changes within a
conserved functional core. RED motif mutations dramatically reduce helicase
activity, and the DRD and ThM, which flank the RED motif, appear structurally
as well as functionally analogous to the MutS mismatch recognition and DNA
polymerase thumb domains. Substrate specificity is altered by DNA damage, such
that AfXPB unwinds dsDNA with 3' extensions, but not blunt-ended dsDNA, unless
it contains a lesion, as shown for CPD or (6-4) photoproducts. Together, these
results provide an unexpected mechanism of DNA unwinding with implications for
XPB damage verification in nucleotide excision repair.
PMID:
16600867 [PubMed - in process
|
Proc
Natl Acad Sci U S A. 2006 Mar 14;103(11):4056-61. Epub 2006 Mar 6. |
Repair of DNA-polypeptide crosslinks by human
excision nuclease.
Reardon JT, Sancar A.
Department
of Biochemistry and Biophysics, University of North Carolina School of
Medicine, Chapel Hill, NC 27599, USA.
DNA-protein crosslinks are
relatively common DNA lesions that form during the physiological processing of
DNA by replication and recombination proteins, b y side reactions of base
excision repair enzymes, and by cellular exposure to bifunctional DNA-damaging
agents such as platinum compounds. The mechanism by which pathological
DNA-protein crosslinks are repaired in humans is not known. In this study, we
investigated the mechanism of recognition and repair of protein-DNA and
oligopeptide-DNA crosslinks by the human excision nuclease. Under our assay
conditions, the human nucleotide excision repair system did not remove a 16-kDa
protein crosslinked to DNA at a detectable level. However, 4- and 12-aa-long
oligopeptides crosslinked to the DNA backbone were recognized by some of the
damage recognition factors of the human excision nuclease with moderate
selectivity and were excised from DNA at relatively efficient rates. Our data
suggest that, if coupled with proteolytic degradation of the crosslinked
protein, the human excision nuclease may be the major enzyme system for
eliminating protein-DNA crosslinks from the genome.
PMID: 16537484
[PubMed - indexed for MEDLINE]
|
J
Biol Chem. 2006 Mar 8; [Epub ahead of print] |
Cullin 4A-mediated proteolysis of DDB2 protein at
DNA damage sites regulates in vivo lesion recognition by XPC.
El-Mahdy MA, Zhu Q, Wang QE, Wani G, Praetorius-Ibba M, Wani AA.
Radiology/Medical
Biochemistry, The Ohio State University, Columbus, OH
43210.
Xeroderma pigmentosum complement-ation group E gene
product, damaged DNA binding protein 2, is a subunit of DDB heterodimeric
protein complex with high specificity for binding to a variety of DNA
helix-distorting lesions. DDB is believed to play a role in the initial step of
damage recognition in mammalian nucleotide excision repair of ultraviolet light-induced
photolesions. It has been shown that DDB2 is rapidly degraded after cellular UV
irradiation. However, the relevance of DDB2 degradation to its functionality in
NER is still unknown. Here, we provide evidence that Cullin 4A, a key component
of CUL-4A-based ubiquitin ligase, mediates DDB2 degradation at the damage sites
and regulates the recruitment of XPC and the repair of cyclobutane pyrimidine
dimers. We show that CUL-4A can be identified in an UV-responsive protein
complex containing both DDB subunits. CUL-4A was visualized in localized
UV-irradiated sites together with DDB2 and XPC. Degradation of DDB2 could be
blocked by silencing CUL-4A using siRNA or by treating cells with proteasome
inhibitor MG132. This blockage resulted in prolonged retention of DDB2 at the
subnuclear DNA damage foci within micropore irradiated cells. Knockdown of
CUL-4A also decreased recruitment of the damage recognition factor, XPC, to the
damaged foci and concomitantly reduced the removal of CPD from the entire genome.
These results suggest that CUL-4A mediates the proteolytic degradation of DDB2
and that this degradation event, initiated at the lesion sites, regulates
damage recognition by XPC during the early steps of NER.
PMID:
16527807 [PubMed - as supplied by publisher]
|
Carcinogenesis.
2006 Mar 7; [Epub ahead of print] |
Polymorphisms in DNA damage binding protein 2
(DDB2) and susceptibility of primary lung cancer in Chinese: a case-control
study.
Hu Z, Shao M
, Yuan J, Xu L, Wang F, Wang Y, Yuan W, Qian J, Ma H, Wang Y, Liu H, Chen W, Yang L, Jing G, Huo X, Chen F, Jin L, Wei Q, Huang W, Lu D, Wu T, Shen H.
Department
of Epidemiology and Biostatistics, Cancer Research Center of Nanjing Medical
University, Nanjing 210029, China.
DNA damage binding protein 2
(DDB2) is one of the major DNA repair proteins involved in the nucleotide
excision repair (NER) pathway. Mutations in the DDB2 gene can cause a
repair-deficiency syndrome xeroderma pigmentosum group E (XPE). Because tobacco
carcinogens can cause DNA damage that is repaired by NER and suboptimal NER
capacity is reported to be associated with lung cancer risk, we hypothesized
that common variants in the DDB2 gene are associated with lung cancer risk. To
test this hypothesis, we conducted a case-control study of 1010 patients with
incident lung cancer and 1011 cancer-free controls and genotyped two DDB2
single nucleotide polymorphisms (SNPs) (rs830083 and rs3781620) that are in
linkage disequilibrium with other untyped SNPs. We found that compared with the
rs830083CC, subjects carrying the heterozygous rs830083CG genotype had a
significantly 1.31-fold increased risk of lung cancer (95% CI 1.08-1.60) and
those carrying the homozygous rs830083GG genotype had a non-significantly 1.22-fold
elevated risk (95% CI 0.89-1.67). In addition, effects of the combined
rs830083CG/GG variant genotypes were more evident in young subjects, heavy
smokers, and subjects with a positive family history of cancer. These findings
indicate, for the first time, that the DDB2 rs830083 polymorphism may
contribute to the etiology of lung cancer. Further functional studies on this
SNP and/or related variants are warranted to elucidate the underlying molecular
mechanisms of the association.
PMID: 16522664 [PubMed - as
supplied by publisher]
|
DNA
Repair (Amst). 2006 Mar 4; [Epub ahead of print] |
UV-induced RPA phosphorylation is increased in the
absence of DNA polymerase eta and requires DNA-PK.
Cruet-Hennequart S,
Coyne S, Glynn MT, Oakley GG, Carty MP.
DNA
Damage Response Laboratory, Department of Biochemistry and National Centre for
Biomedical Engineering Science, National University of Ireland, Galway, Galway
City, Ireland.
Signaling from arrested replication forks plays a
role in maintaining genome stability. We have investigated this process in xeroderma
pigmentosum variant cells that carry a mutation in the POLH gene and lack
functional DNA polymerase eta (poleta). Poleta is required for error-free
bypass of UV-induced cyclobutane pyrimidine dimers; in the absence of poleta in
XPV cells, DNA replication is arrested at sites of UV-induced DNA damage, and
mutagenic bypass of lesions is ultimately carried out by other, error-prone,
DNA polymerases. The present study investigates whether poleta expression
influences the activation of a number of UV-induced DNA damage responses. In a
stably transfected XPV cell line (TR30-9) in which active poleta can be induced
by addition of tetracycline, expression of poleta determines the extent of DNA
double-strand break formation following UV-irradiation. UV-induced
phosphorylation of replication protein A (RPA), a key DNA-binding protein
involved in DNA replication, repair and recombination, is increased in cells
lacking poleta compared to when poleta is expressed in the same cell line. To
identify the protein kinase responsible for increased UV-induced
hyperphosphorylation of the p34 subunit of RPA, we have used NU7441, a specific
small molecule inhibitor of DNA-PK. DNA-PK is necessary for RPA p34
hyperphosphorylation, but DNA-PK-mediated phosphorylation is not required for
recruitment of RPA p34 into nuclear foci in response to UV-irradiation. The
results demonstrate that activation of a UV-induced DNA damage response
pathway, involving phosphorylation of RPA p34 by DNA-PK, is enhanced in cells
lacking poleta.
PMID: 16520097 [PubMed - as supplied by publisher]
|
J
Immunol. 2006 Mar 1;176(5):2896-901. |
IL-18 reduces ultraviolet radiation-induced DNA
damage and thereby affects photoimmunosuppression.
Schwarz A, Maeda A, Stander S, van Steeg H, Schwarz T.
Department
of Dermatology, University Kiel, Kiel, Germany.
UV-induced DNA
damage has been recognized as the major molecular trigger for
photoimmunosuppression. IL-12 prevents UV-induced immunosuppression via its
recently discovered capacity to reduce DNA damage presumably via induction of
DNA repair. Because IL-18 shares some biological activities with IL-12 we
studied the effect of IL-18 on UV-induced DNA damage and immunosuppression.
IL-18 reduced UV-induced apoptosis of keratinocytes and supported long-term
cell survival on UV exposure. Injection of IL-18 into mice that were exposed to
UV radiation significantly lowered the number of apoptotic keratinocytes.
Accordingly, radiation immunohistochemistry revealed reduced amounts of DNA damage
in epidermal cells upon injection of IL-18. These effects were not observed in
DNA repair-deficient (XpaKO) mice, indicating that IL-18 like IL-12 reduces DNA
damage via DNA repair. UV-mediated suppression of the induction of contact
hypersensitivity, which is known to be primarily triggered by DNA damage, was
prevented upon injection of IL-18 before UV exposure in wild-type but not in
XpaKO mice. In contrast to IL-12, IL-18 was not able either in wild-type or in
XpaKO mice to break UV-induced immunotolerance that is mediated via regulatory
T cells rather than in a DNA damage-dependent fashion. This result indicates
that IL-12 is still unique in its capacity to restore immune responses because
of its effect on regulatory T cells. Together, these data identify IL-18 as a
further cytokine that exhibits the capacity to affect DNA repair. Though being
primarily a proinflammatory cytokine through this capacity, IL-18 can also
foster an immune response that is suppressed by UV
radiation.
PMID: 16493047 [PubMed - indexed for MEDLINE]
|
Proc
Natl Acad Sci U S A. 2006 Feb 10; [Epub ahead of print] |
The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in
xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA
sites.
Kapetanaki MG, Guerrero-Santoro J
, Bisi DC, Hsieh CL, Rapic-Otrin V, Levine AS.
Department
of Molecular Genetics and Biochemistry, School of Medicine, and Cancer Institute,
University of Pittsburgh, Hillman Cancer Center, Research Pavilion, Suite 2.6,
5117 Centre Avenue, Pittsburgh, PA 15213.
Xeroderma pigmentosum
(XP) is a heritable human disorder characterized by defects in nucleotide
excision repair (NER) and the development of skin cancer. Cells from XP group E
(XP-E) patients have a defect in the UV-damaged DNA-binding protein complex
(UV-DDB), involved in the damage recognition step of NER. UV-DDB comprises two
subunits, products of the DDB1 and DDB2 genes, respectively. Mutations in the
DDB2 gene account for the underlying defect in XP-E. The UV-DDB complex is a
component of the newly identified cullin 4A-based ubiquitin E3 ligase,
DDB1-CUL4A(DDB2). The E3 ubiquitin ligases recognize specific substrates and
mediate their ubiquitination to regulate protein activity or target proteins
for degradation by the proteasomal pathway. In this study, we have addressed
the role of the UV-DDB-based E3 in NER and sought a physiological substrate. We
demonstrate that monoubiquitinated histone H2A in native chromatin
coimmunoprecipitates with the endogenous DDB1-CUL4A(DDB2) complex in response
to UV irradiation. Further, mutations in DDB2 alter the formation and binding
activity of the DDB1-CUL4A(DDB2) ligase, accompanied by impaired
monoubiquitination of H2A after UV treatment of XP-E cells, compared with
repair-proficient cells. This finding indicates that DDB2, as the substrate
receptor of the DDB1-CUL4A-based ligase, specifically targets histone H2A for
monoubiquitination in a photolesion-binding-dependent manner. Given that the
loss of monoubiquitinated histone H2A at the sites of UV-damaged DNA is
associated with decreased global genome repair in XP-E cells, this study
suggests that histone modification, mediated by the XPE factor, facilitates the
initiation of NER.
PMID: 16473935 [PubMed - as supplied by
publisher]
|
Birth
Defects Res A Clin Mol Teratol. 2006 Feb 9;76(2):129-132 [Epub ahead of
print] |
Neural tube development requires the cooperation of
p53- and Gadd45a-associated pathways.
Patterson AD, Hildesheim J, Fornace AJ Jr, Hollander MC.
National
Institutes of Health-George Washington University Graduate Partnerships Program
in Genetics, Center for Cancer Research, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland.
BACKGROUND: Numerous
genetically engineered mouse models for neural tube defects (NTDs) exist, and
some of the implicated proteins are functionally related. For example, the
growth arrest and DNA damage-inducible protein Gadd45a and tumor suppressor p53
are functionally similar, and both are involved in neural tube development
(Gadd45a- and Trp53-null embryos show low levels of exencephaly). To assess their
roles in neural tube development, we generated double-null mice from Gadd45a-
and Trp53-null mice, as well as from cyclin-dependent kinase inhibitor (Cdkn1a)
(p21)-null and xeroderma pigmentosum group C (XPC)-null mice that do not show
spontaneous exencephaly. METHODS: Gadd45a-, Trp53-, Cdkn1a-, and XPC-null mice
were crossed to generate several double-null mouse models. Embryos (embryonic
day [ED] 16-18) from the single- and double-null crosses were scored for NTDs.
RESULTS: Deletion of both Gadd45a and Trp53 in mice increased exencephaly
frequencies compared to the deletion of either single gene (34.0% in
Gadd45a/Trp53-null compared to 8.4% and 9.1% in the Gadd45a- and Trp53-null
embryos, respectively). Furthermore, although deletion of another p53-regulated
gene, Cdkn1a, is not associated with exencephaly, in conjunction with Gadd45a
deletion, the exencephaly frequencies are increased (30.5% in the
Gadd45a/Cdkn1a-null embryos) and are similar to those in the Gadd45a/Trp53-null
embryos. Although XPC deletion increased exencephaly frequencies in Trp53-null
embryos, XPC deletion did not increase the exencephaly frequencies in
Gadd45a-null embryos. CONCLUSIONS: The increased genetic liability to
exencephaly in the Gadd45a/Trp53- and Gadd45a/Cdkn1a-null embryos may be
related to the disruption of multiple cellular pathways associated with Gadd45a
and p53. Birth Defects Research (Part A), 2006. (c) 2006 Wiley-Liss,
Inc.
PMID: 16470852 [PubMed - as supplied by publisher]
|
Transgenic
Res. 2005 Dec;14(6):845-57. |
The Effect of DNA Repair Defects on Reproductive
Performance in Nucleotide Excision Repair (NER) Mouse Models: An
Epidemiological Approach.
Tsai PS, Nielen M, van der Horst GT, Colenbrander B, Heesterbeek JA, van Vlissingen JM.
Department
of Farm Animal Health, Faculty of Veterinary Medi cine, Utrecht University,
P.O. Box 80151, 3508, Utrecht, TD, The Netherlands.
In this study,
we used an epidemiological approach to analyze an animal database of DNA repair
deficient mice on reproductive performance in five Nucleotide Excision Repair
(NER) mutant mouse models on a C57BL/6 genetic background, namely CSA, CSB,
XPA, XPC [models for the human DNA repair disorders Cockayne Syndrome (CS) and
xeroderma pigmentosum (XP), respectively] and mHR23B (not associated with human
disease). This approach allowed us to detect and quantify reproductive effects
based on a relatively small number of matings. We measured and quantified the
scale of the effect between factors that might influence reproductive
performance (i.e. age at co-housing, seasons) and reproductive parameters (i.e.
litter size and pairing-to-birth interval -'pbi'). Besides, we detected and
quantified the differences in reproductive performance between wild type mice
and heterozygous/homozygous NER mutant mice. From our analyses, we found
impaired reproduction in heterozygous and homozygous knock out mice; in
particular, reduced litter size and lengthened pbi was related to the NER
mutation-mHR23B, in heterozygous couples, even if they were otherwise
phenotypically normal. Heterozygous mHR23B couples produced a 6.6-fold lower
number of mHR23B(-/-) pups than indicated by Mendelian expectation; other
genetic deficiencies studied were not statistically significant from each other
or wild type controls. We concluded that careful epidemiological evaluations by
analysis of animal database could provide reliable information on reproductive
performance and detect deviations that would remain unnoticed without this.
Also, some managerial aspects of mouse breeding could be
evaluated.
PMID: 16315091 [PubMed - in process]
|
Science.
2005 Dec 16;310(5755):1821-4. |
Ubiquitin-binding
domains in y-family polymerases regulate translesion synthesis.
Bienko M, Green CM, Crosetto N, Rudolf F, Zapart G, Coull B, Kannouche P, Wider G, Peter M, Lehmann AR, Hofmann K, Dikic I.
Institute
for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7,
60590 Frankfurt, Germany.
Translesion synthesis (TLS) is the major
pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage,
ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of
the lesion by directing the replication machinery into the TLS pathway. Yet,
how this modification is recognized and interpreted in the cell remains
unclear. Here we describe the identification of two ubiquitin (Ub)-binding
domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS
polymerases (pols). These domains are required for binding of poleta and
poliota to ubiquitin, their accumulation in replication factories, and their
interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of poleta is
essential to efficiently restore a normal response to ultraviolet irradiation
in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that
Ub-binding domains of Y-family polymerases play crucial regulatory roles in
TLS.
PMID: 16357261 [PubMed - in process]
|
Pediatr
Int. 2005 Dec;47(6):653-657. |
Primary malignant skin tumors in children:
Etiology, treatment and prognosis.
Varan A, Gokoz A
, Akyuz C, Kutluk T, Yalcin B, Koksal Y, Buyukpamukcu M.
Department
of Pediatric Oncology, Hacettepe University, Institute of Oncology, Ankara,
Turkey.
Abstract Objective: The aim of the study was to evaluate
the etiology, treatment and prognosis of the malignant skin tumors in children.
Methods: Twenty-one patients who had been diagnosed with malignant skin tumors
between 1972 and 2003 were retrospectively analyzed. Age range was 0.5-20 years
(median 9), and the male/female ratio was 12/9. We had nine (42.9%) patients
with malignant melanoma, five (23.8%) with primary skin non-Hodgkin lymphoma,
three (14.3%) with Kaposi sarcoma (KS), two (9.5%) with basal cell carcinoma
(BCC), and two (9.5%) with squamous cell carcinoma (SCC). Results: We could
define the etiologic factors in only nine (42.9%) patients. Two KS cases were
associated with renal transplantation, two cases of malignant melanoma occurred
within the area of giant hairy cell nevus, one melanoma patient previously had
bone marrow transplantation due to Gricelli syndrome, one patient with BCC had
xeroderma pigmentosum and the other BCC had got radiotherapy due to previous
diagnosis of medulloblastoma. One SCC patient also had xeroderma pigmentosum
and the other had previous skin burn. Overall survival rate was 77%. Melanoma
patients were treated successfully with high-dose interferon. Conclusion:
Although malignant skin tumors are rare in childhood, the prognosis is relatively
better than it is for adults. Malignant melanoma was the most frequent tumor.
Forty-three per cent of our patients had an underlying defect in their immune
barriers which is thought to be responsible for the development of their
malignancies.
PMID: 16354219 [PubMed - as supplied by publisher]
|
Proc
Natl Acad Sci U S A. 2005 Dec 12; [Epub ahead of print] |
Ubiquitinated proliferating cell nuclear antigen
activates translesion DNA polymerases {eta} and REV1.
Garg P, Burgers PM.
Department
of Biochemistry and Molecular Biophysics, Washington University School of
Medicine, 660 South Euclid, St. Louis, MO 63110.
In response to
DNA damage, the Rad6/Rad18 ubiquitin-conjugating complex monoubiquitinates the
replication clamp proliferating cell nuclear antigen (PCNA) at Lys-164.
Although ubiquitination of PCNA is recognized as an essential step in
initiating postreplication repair, the mechanistic relevance of this
modification has remained elusive. Here, we describe a robust in vitro system
that ubiquitinates yeast PCNA specifically on Lys-164. Significantly, only
those PCNA clamps that are appropriately loaded around effector DNA by its
loader, replication factor C, are ubiquitinated. This observation suggests
that, in vitro, only PCNA present at stalled replication forks is
ubiquitinated. Ubiquitinated PCNA displays the same replicative functions as
unmodified PCNA. These functions include loading onto DNA by replication factor
C, as well as Okazaki fragment synthesis and maturation by the PCNA-coordinated
actions of DNA polymerase delta, the flap endonuclease FEN1, and DNA ligase I.
However, whereas the activity of DNA polymerase zeta remains unaffected by
ubiquitination of PCNA, ubiquitinated PCNA specifically activates two key
enzymes in translesion synthesis: DNA polymerase eta, the yeast Xeroderma
pigmentosum ortholog, and Rev1, a deoxycytidyl transferase that functions in
organizing the mutagenic DNA replication machinery. We propose that
ubiquitination of PCNA increases its functionality as a sliding clamp to
promote mutagenic DNA replication.
PMID: 16344468 [PubMed - as
supplied by publisher]
|
Mol
Cell. 2005 Dec 9;20(5):793-9. |
Dual Roles for DNA Polymerase eta in Homologous DNA
Recombination and Translesion DNA Synthesis.
Kawamoto T, Araki K
, Sonoda E, Yamashita YM, Harada K, Kikuchi K, Masutani C, Hanaoka F, Nozaki K, Hashimoto N, Takeda S.
CREST,
Japan Science and Technology Agency, Radiation Genetics, Graduate School of
Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501,
Japan.
Chicken B lymphocyte precursors and DT 40 cells diversify
their immunoglobulin-variable (IgV) genes through homologous recombination
(HR)-mediated Ig gene conversion. To identify DNA polymerases that are involved
in Ig gene conversion, we created DT40 clones deficient in DNA polymerase eta
(poleta), which, in humans, is defective in the variant form of xeroderma
pigmentosum (XP-V). Poleta is an error-prone translesion DNA synthesis
polymerase that can bypass UV damage-induced lesions and is involved in IgV
hypermutation. Like XP-V cells, poleta-disrupted (poleta) clones exhibited
hypersensitivity to UV. Remarkably, poleta cells showed a significant decrease
in the frequency of both Ig gene conversion and double-strand break-induced HR
when compared to wild-type cells, and these defects were reversed by
complementation with human poleta. Our findings identify a DNA polymerase that
carries out DNA synthesis for physiological HR and provides evidence that a
single DNA polymerase can play multiple cellular roles.
PMID:
16337602 [PubMed - in process]
|
Gan
To Kagaku Ryoho. 2005 Nov;32(12):1895-901. |
[Genetic alterations and
chemoresistance]
[Article in Japanese]
Akiyama S.
Dept.
of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,
Graduate School of Medical and Dental Sciences, Kagoshima
University.
Molecular targeting agents will likely play an
increasing role in the management of cancer.However, resistance to
anti-neoplastic drugs remains a serious obstacle to successful cancer
treatment. Analysis of SNPs and microarray technologies should enable us to
predict toxic responses and sensitivities to anticancer agents of each patient,
and the prediction may permit patient-specific anticancer agents and dosages
that reduce the risk of acute toxicity and emergence of drug-resistant tumors.
The relationships are reviewed between the chemoresistance(chemosensitivity)
and polymorphisms, tumor gene expression profiles or mutations of targeted
molecules that confer resistance to molecular target
therapy.
Publication Types:
á Review
PMID: 16282723
[PubMed - indexed for MEDLINE]
|
Actas
Dermosifiliogr. 2005 Nov;96(9):586-8. |
[De
Sanctis-Cacchione syndrome]
[Article in Spanish]
Roson E, Garcia-Doval I, de la Torre C, Feal C, Cruces M.
Servicio
de Dermatologia, Hospital Provincial, Complejo Hospitalario de Pontevedra,
Spain. eroson64@yahoo.es
We present a male patient with
photosensitivity since the earliest months of his life, and pigmented macules
in exposed areas, some showing clinical atypia, which increased in number over
time. Molecular biology studies detected an alteration in DNA repair ability,
so xeroderma pigmentosum was diagnosed. Shortly after birth, low weight,
microcephaly and psychomotor retardation had been observed, but the cause was not
established. The patient progressively showed neurological disorders that
included perceptive deafness, hyporeflexia and areflexia, as well as
choreoathetotic movements. Therefore, we felt that the patient's symptoms fit
De Sanctis-Cacchione syndrome.
PMID: 16476302 [PubMed - in
process]