Molecular
Analysis of DNA Polymerase Eta Gene in Japanese Patients Diagnosed as Xeroderma
Pigmentosum Variant Type.
Tanioka M, Masaki T,
Ono R, Nagano T,
Otoshi-Honda E, Matsumura Y, Takigawa
M, Inui H, Miyachi Y,
Moriwaki S, Nishigori C.
[1] 1Department
of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan [2]
2Department of Dermatology, Graduate School of Medicine, Kyoto University,
Kyoto, Japan.
POLH mutations
were identified in 16 Japanese patients, who were diagnosed, both clinically
and at a cellular level, as being of the xeroderma pigmentosum variant type
(XPV). While all the patients developed skin cancer with an average onset of
the cancer at 45 years, in non-XP Japanese the onset was at over 70 years. All
the cell strains from the patients were normal or slightly hypersensitive to UV
and most of these showed enhanced UV sensitivity when the post-UV colony
formation was performed in the presence of caffeine. Immunoprecipitation
analysis with two kinds of anti-POLH protein antibodies revealed that cells
from 13 patients did not show the 83 kDa POLH band and that cells from one
patient had a faint 83 kDa band. All of these 14 cell strains, without a POLH
band or with a weak POLH band, had mutations in the POLH gene. The IP analysis
of the POLH protein revealed a very useful method for screening the patients
suspected of XPV. Seven mutations in the POLH gene including three novel
mutations were identified. Among the mutations detected, 11 alleles out of 28
(39%) were G490T mutations.Journal of Investigative Dermatology advance online
publication, 8 March 2007; doi:10.1038/sj.jid.5700759.
PMID: 17344931
[PubMed - as supplied by publisher]
------------------------------------------------------------------------
173421922: Nat Clin Pract Neurol. 2007
Mar;3(3):162-72.
Related
Articles, LinkOut
Mechanisms of
disease: DNA repair defects and neurological disease.
Subba Rao K.
Indian Council of
Medical Research Centre for Research on Aging and Brain, Department of
Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad,
India. ksrsl@uohyd.ernet.in
In this Review,
familial and sporadic neurological disorders reported to have an etiological
link with DNA repair defects are discussed, with special emphasis placed on the
molecular link between the disease phenotype and the precise DNA repair defect.
Of the 15 neurological disorders listed, some of which have symptoms of
progeria, six--spinocerebellar ataxia with axonal neuropathy-1, Huntington's
disease, Alzheimer's disease, Parkinson's disease, Down syndrome and
amyotrophic lateral sclerosis--seem to result from increased oxidative stress,
and the inability of the base excision repair pathway to handle the damage to
DNA that this induces. Five of the conditions (xeroderma pigmentosum,
Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome)
display a defect in the nucleotide excision repair pathway, four (Huntington's
disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic
dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in
DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder,
Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes
involved in repairing double-strand breaks. The current overall picture
indicates that oxidative stress is a major causative factor in genomic
instability in the brain, and that the nature of the resulting neurological
phenotype depends on the pathway through which the instability is normally repaired.
PMID: 17342192
[PubMed - in process]
------------------------------------------------------------------------
173346343: Int J Mol Med. 2007 Apr;19(4):589-96.
Related
Articles, LinkOut
The human POLH
gene is not mutated, and is expressed in a cohort of patients with basal or
squamous cell carcinoma of the skin.
Flanagan AM, Rafferty G, O'neill A, Rynne L,
Kell y J, McCann J,
Carty MP.
Department of
Biochemistry, National University of Ireland, Galway, Ireland.
Skin cancer, the
most common cancer in the general population, is strongly associated with
exposure to the ultraviolet component of sunlight. To investigate the
relationship between DNA damage processing and skin tumour development, we
determined the POLH status of a cohort of skin cancer patients. The human POLH
gene encodes DNA polymerase eta (poleta), which normally carries out accurate
translesion synthesis past the major UV-induced photoproduct, the dithymine
cyclobutane dimer. In the absence of active poleta in xeroderma pigmentosum variant
(XPV) patients, mutations accumulate at sites of UV-induced DNA damage,
providing the initiating step in skin carcinogenesis. Forty patients diagnosed
with skin cancer were genotyped for polymorphisms in the POLH protein-coding
sequence, using glycosylase-mediated polymorphism detection (GMPD) and direct
DNA sequencing of POLH PCR products derived from white blood cell genomic DNA.
All individuals carried the wild-type POLH sequence. No POLH mutations were
identified in genomic DNA from skin tumours derived from 15 of these patients.
As determined by RT-PCR, POLH mRNA was expressed in all normal and skin tumour
tissue examined. Poleta protein was also detectable by Western blotting, in two
matched normal and skin tumour extracts. An alternatively spliced form of POLH
mRNA, lacking exon 2, was more readily detected in skin tissue than in white
blood cells from the same patient. Real-time PCR was used to quantify POLH
expression in matched normal and skin tumour-derived mRNA from a series of
patients diagnosed with either basal or squamous cell carcinoma. Compared to
matched normal skin tissue from the same patient, 1 of 7 SCC, and 4 of 10 BCC
tumours examined showed at least a 2-fold reduction in POLH expression, while 1
of 7 SCC, and 3 of 10 BCC tumours showed at least a 2-fold increase in POLH
expression. Differences in gene expression, rather than sequence changes may be
the main mechanism by which POLH status varies between normal and skin tumours
in the population under investigation. Knowledge of the POLH status in skin
tumours could contribute to an understanding of the role of this gene in the
development of the most common cancer in the general population.
PMID: 17334634
[PubMed - in process]
------------------------------------------------------------------------
New areas of
focus at workshop on human diseases involving DNA repair deficiency and
premature aging.
Kraemer KH, Sander M,
Bohr VA.
Basic Research
Laboratory, Center for Cancer Research, National Cancer Institute, NIH,
Bethesda, MD 20892, USA.
Researchers and
clinicians interested in human diseases of DNA repair deficiency and premature
aging gathered at the National Conference Center in Lansdowne, Virginia on 5-8
September 2006 to attend a workshop co-organized by Vilhelm Bohr (National
Institute of Aging) and Kenneth Kraemer (National Cancer Institute). An
important feature of this workshop was the participation of representatives
from xeroderma pigmentosum (XP), Cockayne Syndrome (CS) and trichothiodystrophy
(TTD) family support groups. Studies presented at the workshop described
important new insights into the phenotypic complexity of XP, CS and TTD,
renewed focus on the neurological manifestations of each of these diseases, as
well as keen interest in the role of oxidative stress and mitochondrial
dysfunction in neurodegenerative processes and normal and/or premature aging.
This workshop report summarizes some of the presentations and outcomes of the
workshop.
Publication
Types:
Clinical
Conference
PMID: 17361460
[PubMed - in process]
------------------------------------------------------------------------
173551812: PLoS Biol. 2007 Mar 13;5(4):e79 [Epub
ahead of print]
Related
Articles, Cited Articles, Free in PMC, LinkOut
An Aromatic
Sensor with Aversion to Damaged Strands Confers Versatility to DNA Repair.
Maillard O, Solyom S,
Naegeli H.
It was not known
how xeroderma pigmentosum group C (XPC) protein, the primary initiator of
global nucleotide excision repair, achieves its outstanding substrate
versatility. Here, we analyzed the molecular pathology of a unique Trp690Ser
substitution, which is the only reported missense mutation in xeroderma
patients mapping to the evolutionary conserved region of XPC protein. The
function of this critical residue and neighboring conserved aromatics was
tested by site-directed mutagenesis followed by screening for excision activity
and DNA binding. This comparison demonstrated that Trp690 and Phe733 drive the
preferential recruitment of XPC protein to repair substrates by mediating an
exquisite affinity for single-stranded sites. Such a dual deployment of
aromatic side chains is the distinctive feature of functional
oligonucleotide/oligosaccharide-binding folds and, indeed, sequence homologies
with replication protein A and breast cancer susceptibility 2 protein indicate
that XPC displays a monomeric variant of this recurrent interaction motif. An
aversion to associate with damaged oligonucleotides implies that XPC protein
avoids direct contacts with base adducts. These results reveal for the first
time, to our knowledge, an entirely inverted mechanism of substrate recognition
that relies on the detection of single-stranded configurations in the undamaged
complementary sequence of the double helix.
PMID: 17355181
[PubMed - as supplied by publisher]
------------------------------------------------------------------------
171313453: Int J Cancer. 2007 Mar 1;120(5):1036-45.
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Polymorphisms
in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple
myeloma patients undergoing autologous bone marrow transplantation.
Vangsted A, Gimsing P,
Klausen TW, Nexo BA,
Wallin H, Andersen P, Hokland P, Lillevang ST, Vogel U.
Department of
Haematology, Herlev University Hospital of Copenhagen, DK-2730 Herlev, Denmark.
anevan01@herlevhosp.kbhamt.dk
Individual
variations in the ability to cope with DNA damage by DNA repair may be
essential for the response to chemotherapy, since cancer cells from patients
with an effective DNA repair may survive treatment. We have studied the effect
on time to treatment failure (TTF) and overall survival (OS) of polymorphism in
the DNA repair genes ERCC1, ERCC2 and XRCC3, and in the apoptotic genes
PPP1R13L and CD3EAP in 348 patients with multiple myeloma undergoing autologous
bone marrow transplantation. Carriers of the variant C-allele of ERCC2 K751Q,
the variant T-allele of XRCC3 T241M and the variant A-allele of CD3EAP G-21A
had a 1.3-fold, 1.8-fold and 1.9-fold longer TTF, respectively, than homozygous
wild type carriers (p = 0.006, p = 0.004, p < 0.001). The polymorphism
CD3EAP G-21A also had significant effect on OS (p < 0.045). The polymorphism
ERCC2 K751Q may to be related to sex, since the prolonged TTF was only seen in
women (p = 0.001). Carriers of the combination of variant alleles of ERCC2
K751Q and XRCC3 T241M had 2.8-fold longer TTF (p = 0.0002).This indicates that
suboptimal repair of both DNA mechanisms favors prolonged TTF and that
polymorphism in ERCC2, XRCC3 and CD3EAP predicts the outcome for patients
treated with autologous stem cell transplantation. Copyright 2006 Wiley-Liss,
Inc.
Publication
Types:
Multicenter Study
Research Support,
Non-U.S. Gov't
PMID: 17131345
[PubMed - indexed for MEDLINE]
------------------------------------------------------------------------
173786881: Pediatr Dev Pathol. 2007
Mar-Apr;10(2):149-52.
Related
Articles
Atypical
fibroxanthoma and squamous cell carcinoma of the conjunctiva in xeroderma
pigmentosum.
Shao L, Newell B,
Quintanilla N.
Patients with
xeroderma pigmentosum (XP) have defective DNA repair and a high predisposition
to developing abnormalities and neoplasia in the sun-exposed areas of the skin
and mucous membranes. The most common tumors reported in patients with XP are
squamous cell carcinomas, basal cell carcinomas, and melanomas. Atypical
fibroxanthoma (AFX) is a pleomorphic tumor that arises predominantly in the
sun-damaged skin of the head and neck regions of the elderly. We describe a
unique case of a 6-year-old African American boy with XP who developed an
atypical fibroxanthoma and 2 squamous cell carcinomas in the conjunctiva. The
clinical and histopathologic findings of AFX are discussed.
PMID: 17378688
[PubMed - in process]
------------------------------------------------------------------------
173749672: Pathobiology. 2006;73(6):295-303.
Related
Articles, LinkOut
Association
between DNA Repair Gene Polymorphisms and p53 Alterations in Japanese Patients
with Muscle-Invasive Bladder Cancer.
Sakano S, Matsumoto H, Yamamoto
Y, Kawai Y, Eguchi S,
Ohmi C, Matsuyama H, Naito K.
Department of
Urology, Yamaguchi University School of Medicine, Ube, Japan .
Objective: DNA
repair enzymes play a vital role in protecting the genome from carcinogens,
several of which can cause mutations in the TP53 gene in bladder cancer. Some
single nucleotide polymorphisms (SNPs) in DNA repair genes reportedly modulate
the repair capacity. This study aimed to clarify the effect of these functional
SNPs on the alteration of p53 in muscle-invasive bladder cancer. Methods: We
investigated the association between SNPs in xeroderma pigmentosum
complementation groups C (XPC), D and G and X-ray repair cross-complementing
group 1 and 3 genes, and p53 expression and allelic imbalance at the TP53 locus
in Japanese patients with muscle-invasive bladder cancer. p53 expression and
the allelic imbalance were evaluated using immunohistochemistry and a
microsatellite marker, respectively. Results: Positive p53 expression was
significantly less frequent in patients with the CC genotype of the XPC gene
than in those with the AA or AC genotype (p = 0.0005). C alleles of the XPC
gene were also less frequent in patients with positive p53 expression (p =
0.01). Conclusion: Our results suggested that the XPC polymorphism might affect
p53 alteration and the molecular pathway defined by the p53 alteration in the
development of muscle-invasive bladder cancer. Copyright (c) 2006 S. Karger AG,
Basel.
PMID: 17374967
[PubMed - in process]
------------------------------------------------------------------------
173731893: J Drugs Dermatol. 2007 Mar;6(3):281-8.
Related
Articles, LinkOut
Xeroderma
pigmentosum: beyond skin cancer.
Lichon V, Amor K.
University of
Illinois, Chicago, IL, USA.
Xeroderma
pigmentosum (XP) is a rare, autosomal-recessive inherited disease that is found
worldwide at a frequency of approximately 1:250,000. XP is caused by a
deficiency in either nucleotide excision repair (NER) or postreplication repair
(PRR), and is characterized by severe actinic changes leading to early onset of
skin cancers, various ocular manifestations, and occasional neurological
abnormalities. Diagnosis is usually made clinically and can be confirmed by
unscheduled DNA synthesis. Early preventative care is the most important
treatment modality. We present a review of the history, clinical
manifestations, pathogenesis, diagnosis, and treatment of XP.
PMID: 17373189
[PubMed - in process]
------------------------------------------------------------------------
174414551: Masui. 2007 Apr;56(4):439-41.
Related
Articles, LinkOut
[Anesthesia
for a patient with xeroderma pigmentosum]
[Article in
Japanese]
Miyazaki R, Nagata T,
Kai T, Takahashi S.
Department of
Anesthesiology and Critical Care Medicine, Kyushu University Hospital, Fukuoka.
A 23-year-old man
with xeroderma pigmentosum underwent laparoscopic cholecystectomy. He
experienced transient worsening of the neurological symptom after anesthesia
with volatile agents in the previous surgery. Because volatile anesthetics
potentially cause genotoxic effects in patients with xeroderma pigmentosum,
this time we chose total ir.travenous anesthesia (TIVA). The intraoperative
management and the post-operative course were uneventful this time. From these
two anesthesia experiences in one patient, we suggest that TIVA is more
appropriate than anesthesia with volatile agents as a method for general
anesthesia for xeroderma pigmentosum patients. Minimum usage of muscle
relaxants under the monitoring of neuromuscular blockade is also recommended,
since xeroderma pigmentosum patients are sensitive to muscle relaxants due to
the neuronal dysfunction and muscle
Publication
Types:
English Abstract
PMID: 17441455
[PubMed - in process]
------------------------------------------------------------------------
173267242: PLoS Biol. 2006 Dec 12;5(1):e2.
Related
Articles, Compound via MeSH, Substance via MeSH, Cited
Articles, Free in PMC, LinkOut
Impaired
genome maintenance suppresses the growth hormone--insulin-like growth factor 1
axis in mice with Cockayne syndrome.
van der
Pluijm I, Garinis GA, Brandt RM,
Gorgels TG, Wijnhoven SW, Diderich
KE, de Wit J, Mitchell JR, van
Oostrom C, Beems R, Niedernhofer LJ, Velasco S, Friedberg EC, Tanaka K, van Steeg H, Hoeijmakers
JH, van der Horst GT.
Department of Gen
etics, Center for Biomedical Genetics, Erasmus University Medical Center,
Rotterdam, The Netherlands.
Cockayne syndrome
(CS) is a photosensitive, DNA repair disorder associated with progeria that is
caused by a defect in the transcription-coupled repair subpathway of nucleotide
excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-)
mutants causes a phenotype that reliably mimics the human progeroid CS
syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive
neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die
before weaning. Mouse liver transcriptome analysis and several physiological
endpoints revealed systemic suppression of the growth hormone/insulin-like
growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased
antioxidant responses, and hypoglycemia together with hepatic glycogen and fat
accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and
naturally aged mouse liver transcriptomes suggested that these changes are intrinsic
to natural ageing and the DNA repair-deficient mice. Importantly, wild-type
mice exposed to a low dose of chronic genotoxic stress recapitulated this
response, thereby pointing to a novel link between genome instability and the
age-related decline of the somatotroph axis.
Publication
Types:
Research Support,
N.I.H., Extramural
Research Support,
Non-U.S. Gov't
PMID: 17326724
[PubMed - indexed for MEDLINE]
------------------------------------------------------------------------
174762811: Leukemia. 2007 May 3; [Epub ahead of
print]
Related
Articles
Role of MTHFR
(677, 1298) haplotype in the risk of developing secondary leukemia after
treatment of breast cancer and hematological malignancies.
Guillem VM, Collado M,
Terol MJ, Calasanz MJ, Esteve J, Gonzalez M, Sanzo C, Nomdedeu J, Bolufer P, Lluch A,
Tormo M.
1Servicio de
Hematologia y Oncologia, Hospital Clinico Universitario de Valencia,
Universidad de Valencia, Valencia, Spain.
Therapy-related
myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring
after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in
chemotherapy/radiotherapy response genes could be related to an increased risk
of developing this neoplasia. We have studied 11 polymorphisms in genes of drug
detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair
xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross
complementing protein (1)), Nijmegen breakage syndrome (1), excision repair
cross-complementing rodent repair deficiency, complementation group (5) and
X-ray repair cross complementing protein (3) and in the methylene
tetrahydrofolate reductase gene (MTHFR(2), 677C>T, 1298A>C), involved in
DNA synthesis. The analyzed groups were a t-MDS/AML patients group (n=81) and a
matched control group (n=64) treated similarly, and they did not develop
t-MDS/AML. We found no significant differences when the groups were compared
globally. However, when analysis was carried out according to the primary
neoplasia involved, a significant association was observed between the MTHFR
haplotype (single nucleotide polymorphisms 677 and 1298) and the risk of
developing t-MDS/AML in the breast cancer patients group (P=0.016) and
cyclophosphamide-treated hematological disease group (P=0.005). Risk haplotype
was different for each case, corresponding to the 677T1298A haplotype after
breast cancer treatment and the 677C1298C haplotype after hematological
malignancy treatment. We postulate that such differences are related to variations
in chemotherapy schemes between hematological and breast cancers and their
differential interaction with the MTHFR route.Leukemia advance online
publication, 3 May 2007; doi:10.1038/sj.leu.2404709.
PMID: 17476281
[PubMed - as supplied by publisher]
------------------------------------------------------------------------
174666262: Mol Cell. 2007 Apr 27;26(2):245-56.
Related
Articles, LinkOut
Distinct Roles
for the XPB/p52 and XPD/p44 Subcomplexes of TFIIH in Damaged DNA Opening during
Nucleotide Excision Repair.
Coin F, Oksenych V, Egly JM.
Institut de
Genetique et de Biologie Moleculaire et Cellulaire, CNRS (UMR7104)/INSERM
(U596)/ULP, BP 163, 67404 Illkirch Cedex, C.U. Strasbourg, France.
Mutations in XPB,
an essential subunit of the transcription/repair factor TFIIH, lead to
nucleotide excision repair (NER) defects and xeroderma pigmentosum (XP). The
role of XPB in NER and the molecular mechanisms resulting in XP are poorly
understood. Here, we show that the p52 subunit of TFIIH interacts with XPB and
stimulates its ATPase activity. A mutation found among XP-B patients (F99S)
weakens this interaction and the resulting ATPase stimulation, thereby
explaining the defect in the damaged DNA opening. We next found that mutations
in the helicase motifs III (T469A) and VI (Q638A) that inhibit XPB helicase
activity preserve the NER function of TFIIH. Our results suggest a mechanism in
which the helicase activity of XPB is not used for the opening and repair of
damaged DNA, which is instead only driven by its ATPase activity, in
combination with the helicase activity of XPD.
PMID: 17466626
[PubMed - in process]
------------------------------------------------------------------------
174666253: Mol Cell. 2007 Apr 27;26(2):231-43.
Related
Articles, LinkOut
XPG Stabilizes
TFIIH, Allowing Transactivation of Nuclear Receptors: Implications for Cockayne
Syndrome in XP-G/CS Patients.
Ito S, Kuraoka I,
Chymkowitch P, Compe E,
Takedachi A, Ishigami C, Coin F, Egly JM,
Tanaka K.
Laboratories for
Organismal Biosystems, Graduate School of Frontier Biosciences, Osaka
University, Osaka 565-0871, Japan.
Mutations in the
human XPG gene give rise to an inherited photosensitive disorder, xeroderma
pigmentosum (XP) associated with Cockayne syndrome (XP-G/CS). The clinical
features of CS in XP-G/CS patients are difficult to explain on the basis of a
defect in nucleotide excision repair (NER). We found that XPG forms a stable
complex with TFIIH, which is active in transcription and NER. Mutations in XPG
found in XP-G/CS patient cells that prevent the association with TFIIH also
resulted in the dissociation of CAK and XPD from the core TFIIH. As a
consequence, the phosphorylation and transactivation of nuclear receptors were
disturbed in XP-G/CS as well as xpg(-/-) MEF cells and could be restored by
expression of wild-type XPG. These results provide an insight into the role of
XPG in the stabilization of TFIIH and the regulation of gene expression and
provide an explanation of some of the clinical features of XP-G/CS.
PMID: 17466625
[PubMed - in process]
------------------------------------------------------------------------
174387034: Acta Oncol. 2007;46(1):31-41.
Related
Articles, LinkOut
Polymorphisms
in XPD, XPC and the risk of death in patients with urinary bladder neoplasms.
Sanyal S, De Verdier PJ, Steineck
G, Larsson P, Onelov E,
Hemminki K, Kumar R.
Division of
Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska
Institute, Stockholm, Sweden.
We conducted a
follow-up study on 311 patients with urinary bladder neoplasms to investigate
the association of polymorphisms in DNA repair and cell growth regulatory genes
with the clinical outcomes of this disease. We found that patients carrying the
variant allele of XPD (K751Q) polymorphism were at lower risk of death (p =
0.04) than the noncarriers. Patients that were simultaneous carriers of variant
alleles from XPD (K751Q) and XPC (K939Q) polymorphisms, showed lower risk of
death than the other patients (p = 0.001). The variant allele carriers of MSH6
(G39E) polymorphism showed a higher risk for highly malignant disease (TaG3
+T1) than the non-carriers (p = 0.03). The variant allele carriers of XRCC1
(R399Q) polymorphism showed lower risk for recurrence (TaG2; p = 0.05) and
death (T2+; p = 0.03) after instillation and radiotherapy than the
non-carriers. After radiotherapy, an inverse association of the variant allele
of OGG1 (S326C) polymorphism was observed with the risk of death (T2 +; p =
0.04). A significant low-risk for stage progression (p = 0.03) was observed in
patients carrying the variant allele of H-ras (H27H) polymorphism. Our results
are consistent with the notion that the XPD (K751Q) polymorphism either
individually or in combination with the XPC (K939Q) polymorphism modulates the
risk of death in patients with urinary bladder neoplasms.
Publication
Types:
Research Support,
Non-U.S. Gov't
PMID: 17438703
[PubMed - indexed for MEDLINE]
------------------------------------------------------------------------
171184885: Lung Cancer. 2007 Mar;55(3):303-11. Epub
2006 Nov 21.
Related
Articles, LinkOut
Increased
expression and activity of repair genes TDP1 and XPF in non-small cell lung
cancer.
Liu C, Zhou S,
Begum S, Sidransky D, Westra WH, Brock M,
Califano JA.
Department of
Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Division, Johns
Hopkins Medical Institutions, Baltimore, MD, United States.
Resistance to
camptothecin (CPT), a topoisomerase I (Top1) inhibitor, is frequently
encountered in non-small cell lung cancer ( NSCLC) and CPT resistance is linked
with TDP1, an enzyme capable of cleaving the covalent linkage between
stabilized Top1 with DNA. The aim of this study is to evaluate the in vivo
expression level of TDP1, as well as parallel repair pathway components XPF and
MUS81, in primary NSCLC. We collected 30 un-matched and 4 NSCLC samples matched
with normal lung tissue and 8 samples of non-neoplastic lung tissue from
patients with and without lung cancer, and determined the protein expression of
these three genes using Western blot and TDP1 activity by a specific enzymatic
assay. Both TDP1 and XPF were overexpressed in over 50% of NSCLC tissues, with
wide ranges of expression levels. MUS81 did not exhibit alteration in
expression. Overexpression of TDP1 and XPF is common in NSCLC, and is therefore
of interest as a possible contributor to drug resistance in NSCLC.
Publication
Types:
Research Support,
N.I.H., Extramural
Research Support,
Non-U.S. Gov't
PMID: 17118488
[PubMed - indexed for MEDLINE]
------------------------------------------------------------------------
175103961: Cancer Res. 2007 May 15;67(10):4695-9.
The combined
effects of xeroderma pigmentosum C deficiency and mutagens on mutation rates in
the mouse germ line.
Miccoli L, Burr KL,
Hickenbotham P, Friedberg EC, Angulo J
F, Dubrova YE.
Commissariat a
l'Energie Atomique, Laboratoire de Genetique de la Radiosensibilite, Institut
de Radiobiologie Cellulaire et Moleculaire, Direction des Sciences du Vivant,
Fontenay aux Roses, France.
Spontaneous and
induced mutation rates at two expanded simple tandem repeat (ESTR) loci were
studied in the germ line of xeroderma pigmentosum group C (Xpc) knockout mice
defective in global genome nucleotide excision repair. Spontaneous and
radiation-induced mutation rates in homozygous Xpc(-/-) males were
significantly higher than those in isogenic wild-type (Xpc(+/+)) and
heterozygous (Xpc(+/-)) mice. In contrast, exposure to the monofunctional
alkylating agent ethylnitrosourea resulted in similar increases in ESTR mutation
rates across all genotypes. ESTR mutation spectra in the germ line of Xpc(-/-),
Xpc(+/-) and Xpc(+/+) did not differ. Considering these data and the results of
other publications, we propose that the Xpc-deficient mice possess a mutator
phenotype in their germ line and somatic tissues that may significantly enhance
carcinogenesis across multiple tissues. [Cancer Res 2007;67(10):4695-9].
PMID: 17510396
[PubMed - in process]
------------------------------------------------------------------------
175103832: Cancer Res. 2007 May 15;67(10):4578-85.
Attenuated
expression of xeroderma pigmentosum group C is associated with critical events
in human bladder cancer carcinogenesis and progression.
Chen Z, Yang J,
Wang G, Song B,
Li J, Xu Z.
Urology Institute
of People's Liberation Army, Southwest Hospital, and Department of Biochemistry
and Molecular Biology, The Third Military Medical University, Chongqing, P.R.
China.
Xeroderma
pigmentosum group C (XPC) is an important DNA damage recognition protein that
binds to damaged DNA at a very early stage during DNA repair. The XPC protein
is also involved in DNA damage-induced cell cycle checkpoint regulation and
apoptosis. XPC defects are associated with many types of solid tumors. The
mechanism of the XPC protein in cancer progression, however, remains unclear.
In this report, we showed the strong correlation between bladder cancer
progression and attenuated XPC protein expression using tissues derived from
patients with bladder cancer. The results obtained from our immunohistochemical
studies further revealed a strong correlation of XPC deficiency, p53 mutation,
and the degree of malignancy of bladder tumors. In addition, the results
obtained from our studies have also shown that HT1197 bladder cancer cells,
which carry a low-level XPC protein, exhibited a decreased DNA repair
capability and were resistant to cisplatin treatment. When an XPC gene
cDNA-expression vector was stably transfected into the HT1197 cells, however,
the cisplatin treatment-induced apoptotic cell death was increased. Increased
p53 and p73 responses following cisplatin treatment were also observed in
HT1197 cells stably transfected with XPC cDNA. Taken together, these results
suggest that XPC deficiency is an important contributing factor in bladder tumor
progression and bladder cancer cell drug resistance. [Cancer Res
2007;67(10):4578-85].
PMID: 17510383
[PubMed - in process]
------------------------------------------------------------------------
175099503: DNA Repair (Amst). 2007 May 15; [Epub ahead
of print]
Influence of
XPB helicase on recruitment and redistribution of nucleotide excision repair
proteins at sites of UV-induced DNA damage.
Oh KS, Imoto K,
Boyle J, Khan SG,
Kraemer KH.
Basic Research
Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda,
MD, USA.
The XPB DNA
helicase, a subunit of the basal transcription factor TFIIH, is also involved
in nucleotide excision repair (NER). We examined recruitment of NER proteins in
XP-B cells from patients with mild or severe xeroderma pigmentosum (XP) having
different XPB mutations using local UV-irradiation through filters with 5mum
pores combined with fluorescent antibody labeling. XPC was rapidly recruited to
UV damage sites containing DNA photoproducts (cyclobutane pyrimidine dimers,
CPD) in all the XP-B and normal cells, thus reflecting its role in damage
recognition prior to the function of XPB. Cells from the mild XP-B patients,
with a missense mutation, showed delayed recruitment of all NER proteins except
XPC to UV damage sites, demonstrating that this mutation impaired localization
of these proteins. Surprisingly, in cells from severely affected patients, with
a C-terminal XPB mutation, XPG and XPA proteins were normally recruited to UV
damage sites demonstrating that this mutation permits recruitment of XPG and
XPA. In marked contrast, in all the XP-B cells recruitment of XPF was absent
immediately after UV and was delayed by 0.5 and 3h in cells from the mild and
severely affected XP patients, respectively. Redistribution of NER proteins was
nearly complete in normal cells by 3h but by 24h redistribution was only
partially present in cells from mild patients and virtually absent in cells
from the severely affected patients. Ineffectual repair of UV-induced
photoproducts resulting from delayed recruitment and impaired redistribution of
NER proteins may contribute to the markedly increased frequency of skin cancer
in XP patients.
PMID: 17509950
[PubMed - as supplied by publisher]
------------------------------------------------------------------------
175084094: Cancer. 2007 May 16; [Epub ahead of print]
Related
Articles
Reduced XPC
messenger RNA level may predict a poor outcome of patients with nonsmall cell
lung cancer.
Wu YH, Cheng YW,
Chang JT, Wu TC, Chen CY, Lee H.
Institute of
Medical and Molecular Toxicology, Chung Shan Medical University, Taichung,
Taiwan, Republic of China.
BACKGROUND.:
Homologous deletion of the xeroderma pigmentosum complementary group C (XPC)
repair gene frequently causes lung adenocarcinoma in mice, suggesting that an
XPC defect may play a critical role in lung tumorigenesis. The current study
attempted to determine whether reduced XPC mRNA levels predict the clinical
outcome of lung cancer patients. METHODS.: XPC, p27(kip) (cdk inhibitory protein),
and S-phase kinase-associated protein (skp2) levels were evaluated by Western
blot analysis in a series of lung cancer cell lines with different invasive
abilities. Migration and invasive abilities were measured using a modified
Boyden chamber without and with Matrigel, respectively. To test whether XPC
affects cell invasive ability, XPC gene protein expression was reduced in low
invasive cells by RNA interference (RNAi) and assayed with Boyden chamber. XPC
mRNA levels in 126 nonsmall cell lung cancers (NSCLCs) were examined by
real-time-reverse-transcriptase polymerase chain reaction (RT-PCR). The
prognostic value of XPC mRNA expression was statistically analyzed by the
Kaplan-Meier method and Cox proportional hazards regression. RESULTS.: The expression
of XPC was reduced with increasing invasive potential in CL1-series lung cancer
cell lines. When the XPC level was reduced by RNAi, cell migration and
invasiveness increased markedly; the increased invasiveness may be caused by
decreased expression of p27(kip) and increased expression of skp2 and E2F
transcription factor 1. To determine whether reduced XPC expression was
correlated with tumor aggressiveness and poor patient survival, XPC mRNA levels
were evaluated by real-time RT-PCR. Kaplan-Meier analysis demonstrated that the
median survival of patients with lower XPC mRNA levels was shorter compared
with patients with higher XPC mRNA levels (P = .0440). Cox regression analysis
further indicated that XPC mRNA level may act as an independent prognostic
factor for NSCLC patients (P = .014). CONCLUSIONS.: The results of the current
study suggest that reduced XPC mRNA level may constitute an independent
prognostic factor for NSCLC patients. Cancer 2007. (c) 2007 American Cancer
Society.
PMID: 17508409 [PubMed
- as supplied by publisher]
------------------------------------------------------------------------
174983155: BMC Cancer. 2007 May 13;7(1):81 [Epub
ahead of print]
Related
Articles, LinkOut
Sequence
variations in DNA repair gene XPC is associated with lung cancer risk in a
Chinese population: a case-control study.
Bai Y, Xu L, Yang X, Hu Z, Yuan J, Wang F,
Hua M, Yuan W,
Qian J, Ma H, Wang Y,
Liu H, Chen W,
Yang L, Jing G,
Huo X, Chen F,
Liu Y, Jin L, Wei Q, Huang W,
Shen H, Lu D, Wu T.
ABSTRACT:
BACKGROUND: The nucleotide excision repair (NER) protein, xeroderma pigmentosum
C (XPC), participates in recognizing DNA lesions and initiating DNA repair in
response to DNA damage. Because mutations in XPC cause a high risk of cancer in
XP patients, we hypothesized that inherited sequence variations in XPC may
alter DNA repair and thus susceptibility to cancer. METHODS: In this
hospital-based case-control study, we investigated five XPC tagging, common
single nucleotide polymorphisms (tagging SNPs) in 1,010 patients with newly
diagnosed lung cancer and 1,011 matched cancer free controls in a Chinese
population. RESULTS: In individual tagging SNP analysis, we found that
rs3731055AG+AA variant genotypes were associated with a significantly decreased
risk of lung adenocarcinoma [adjusted odds ratio (OR), 0.71; 95% confidence
interval (CI), 0.56 - 0.90] but an increased risk of small cell carcinomas
[adjusted OR, 1.79; 95% CI, 1.05 - 3.07]. Furthermore, we found that haplotype
ACCCA was associated with a decreased risk of lung adenocarcinoma [OR, 0.78;
95% CI, 0.62 - 0.97] but an increased risk of small cell carcinomas [OR, 1.68;
95% CI, 1.04 - 2.71], which reflected the presence of rs3731055A allele in this
haplotype. Further stratified analysis revealed that the protective effect of
rs3731055AG+AA on risk of lung adenocarcinoma was more evident among young
subjects and never smokers. CONCLUSION: These results suggest that inherited
sequence variations in XPC may modulate risk of lung cancer, especially lung adenocarcinoma,
in Chinese populations. However, these findings need to be verified in larger
confirmatory studies with more comprehensively selected tagging SNPs.
PMID: 17498315
[PubMed - as supplied by publisher]
------------------------------------------------------------------------
[Effect of
estrogen on nucleotide excision repair of N2a neroblastoma cells]
[Article in
Japanese]
Yoshioka A, Yamamoto A, Mori T, Nakamura Y, Morikawa
M, Yoshino H, Kiuchi K,
Makinodan M, Kishimoto T.
Department of
Psychiatry,,
Until now reduced
estrogen level has been considered to affect some psychiatric symptoms, because
there are sex differences in onset of Schizophrenia and Alzheimer's disease.
Estrogen is associated with cognitive functions, and it has been reported to
protect oxidative damage of DNA related to base excision repair (BER). Some
patients with Xeroderma Pigmentosum, who have normal BER and impaired
nucleotide excision repair (NER), are known to be suffering from mental
retardation. Therefore we hypothesized that impaired NER was partly associated
with pathology of mental disorder and investigated the effects of estrogen on
NER for ultraviolet-induced DNA damage. The N2a neuroblastoma cell line was
used as a representative of neuronal cells and 17p-estradiol was selected as
one of the most active estrogen derivatives. There were no significant effects
of 17p-estradiol on prevention of DNA damage, promotion of DNA repair, or cell
survival at the concentration of 0-0.1 microM 17p-estradiol (below cytotoxicity
level). These results described that estrogen might not directly affect NER
except through another DNA repair system.
Publication
Types:
English Abstract
PMID: 17515114
[PubMed - in process]
------------------------------------------------------------------------
175129212: Chem Biol Interact. 2007 Apr 19; [Epub
ahead of print]
Related
Articles, LinkOut
Preferential
binding of human XPA to the mitomycin C-DNA interstrand crosslink and
modulation by arsenic and cadmium.
Mustra DJ, Warren AJ,
Wilcox DE, Hamilton JW.
Department of
Pharmacology & Toxicology, Dartmouth Medical School, Hanover, NH
03755-3835, United States; Center for Environmental Health Sciences, Dartmouth
Medical School, Hanover, NH 03755-3851, United States.
The Xeroderma
Pigmentosum A (XPA) protein is involved in the DNA damage recognition and
repair complex formation steps of nucleotide excision repair (NER), and has
been shown to preferentially bind to various forms of DNA damage including
bulky lesions. DNA interstrand crosslinks are of particular interest as a form
of DNA damage, since these lesions involve both strands of duplex DNA and
present special challenges to the repair machinery, and mitomycin C (MMC) is
one of several useful cancer chemotherapy drugs that induce these lesions.
Purified XPA and the minimal DNA-binding domain of XPA are both fully capable
of preferentially binding to MMC-DNA interstrand crosslinks in the absence of
other proteins from the NER complex. Circular dichroism (CD) and gel shift
assays were used to investigate XPA-DNA binding and to assess changes in
secondary structure induced as a consequence of the interaction of XPA with
model MMC-crosslinked and unmodified DNAs. These studies revealed that while
XPA demonstrates only a modest increase in affinity for adducted DNA, it adopts
a different conformation when bound to MMC-damaged DNA than when bound to
undamaged DNA. This change in conformation may be more important in recruiting
other proteins into a competent NER complex at damaged sites than preferential
binding per se. Arsenic had little effect on XPA binding even at toxic
concentrations, whereas cadmium reduced XPA binding to DNA to 10-15% that of
Zn-XPA, and zinc addition could only partially restore activity. In addition,
there was little or no change in conformation when Cd-XPA bound MMC-crosslinked
DNA even though it demonstrated preferential binding, which may contribute to
the mechanism by which cadmium can act as a co-mutagen and co-carcinogen.
PMID: 17512921
[PubMed - as supplied by publisher]
------------------------------------------------------------------------
172595433: Eukaryot Cell. 2007 Apr;6(4):641-9. Epub
2007 Jan 26.
Related
Articles, LinkOut
Spliced leader
RNA gene transcription in Trypanosoma brucei requires transcription factor
TFIIH.
Lee JH, Nguyen TN,
Schimanski B, Gunzl A.
Department of
Genetics and Developmental Biology, University of Connecticut Health Center,
263 Farmington Avenue, Farmington, CT 06030-3301, USA.
Trypanosomatid
parasites share a gene expression mode which differs greatly from that of their
human and insect hosts. In these unicellular eukaryotes, protein-coding genes
are transcribed polycistronically and individual mRNAs are processed from
precursors by spliced leader (SL) trans splicing and polyadenylation. In trans
splicing, the SL RNA is consumed through a transfer of its 5'-terminal part to
the 5' end of mRNAs. Since all mRNAs are trans spliced, the parasites depend on
strong and continuous SL RNA synthesis mediated by RNA polymerase II. As essential
factors for SL RNA gene transcription in Trypanosoma brucei, the general
transcription factor (GTF) IIB and a complex, consisting of the TATA-binding
protein-related protein 4, the small nuclear RNA-activating protein complex,
and TFIIA, were recently identified. Although T. brucei TFIIA and TFIIB are
extremely divergent to their counterparts in other eukaryotes, their
characterization suggested that trypanosomatids do form a class II
transcription preinitiation complex at the SL RNA gene promoter and harbor
orthologues of other known GTFs. TFIIH is a GTF which functions in
transcription initiation, DNA repair, and cell cycle control. Here, we
investigated whether a T. brucei TFIIH is important for SL RNA gene
transcription and found that silencing the expression of the highly conserved
TFIIH subunit XPD in T. brucei affected SL RNA gene synthesis in vivo, and
depletion of this protein from extract abolished SL RNA gene transcription in
vitro. Since we also identified orthologues of the TFIIH subunits XPB, p52/TFB2,
and p44/SSL1 copurifying with TbXPD, we concluded that the parasite harbors a
TFIIH which is indispensable for SL RNA gene transcription.
Publication
Types:
Research Support,
N.I.H., Extramural
Research Support,
Non-U.S. Gov't
PMID: 17259543 [PubMed
- indexed for MEDLINE]
------------------------------------------------------------------------
168896961: Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za
Zhi. 2006 Jul;24(7):390-3.
Related
Articles, LinkOut
[Association
between polymorphisms of XPD gene and susceptibility to chronic benzene
poisoning]
[Article in
Chinese]
Huang HL, Xu JN, Wang QK, Wang YW,
Yang M, Chen Y,
Li GL.
Institute of
Occupational Health and Poison Control, Chinese Center for Disease Control and
Prevention, Beijing 100050, China.
OBJECTIVE: To
explore the relationship between genetic polymorphisms of XPD gene and
susceptibility to chronic benzene poisoning. METHODS: A case control study was
conducted. Eighty patients diagnosed with chronic benzene poisoning and 62
workers occupationally exposed to benzene who were engaged in the same working
time and job title as patients were investigated. PCR-RFLP was used for
detecting the single nucleotide polymorphisms (SNPs) on codon156, codon312 and
codon751 of XPD gene. RESULTS: There was a 2.903 times (95% CI: 1.054 - 7.959,
P = 0.039 2) increased risk of chronic benzene poisoning in the subjects
carrying XPD 751Gln variant allele compared with those carrying XPD 751Lys/Lys
genotype, after adjusted for sex, length of service, smoking and drinking
status. CONCLUSION: The subjects with XPD 751Gln variant allele are more
susceptive to benzene.
Publication
Types:
English Abstract
Research Support,
Non-U.S. Gov't
PMID: 16889696
[PubMed - indexed for MEDLINE]
------------------------------------------------------------------------