Xeroderma Pigmentosum Complementation Group F Research Articles

Chemical-Genetic Interactions of Bacopa monnieri Constituents in Cells Deficient for the DNA Repair Endonuclease RAD1 Appear Linked to Vacuolar Disruption.

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. Bacopa monnieri extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a Saccharomyces cerevisiae model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for B. monnieri extracts to limit proliferation and promote an apoptosis-like event in RAD1 deleted yeast was not elucidated. Our current analysis has revealed that B. monnieri extracts have the capacity to promote mutations in rad1∆ cells. In addition, the effects of B. monnieri extracts on rad1∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of RAD1 in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of B. monnieri extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from B. monnieri identified a chemical-genetic interaction between bacopasaponin C and rad1∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.

Impact of XPF rs2276466 polymorphism on cancer susceptibility: a meta-analysis.

Association between the xeroderma pigmentosum complementation group F (XPF)rs2276466 located in the excision repair cross complementation group 4 (ERCC4) gene and cancer susceptibility has been widely investigated. However, results thus far have remained controversial. A meta-analysis was performed to identify the impact of this polymorphism on cancer susceptibility. PubMed, Embase and Science-Web databases were searched systematically up to May 20, 2018, to obtain all the records evaluating the association between the rs2276466 polymorphism and the risk of all types of cancers. We used the odds ratio (OR) as a measure of effect, and pooled the data in a Mantel-Haenszel weighed random-effects meta-analysis to provide a summary estimate of the impact of this polymorphism on gastrointestinal cancer, neurogenic cancer and other cancers (breast cancer and SCCHN). All the analyses were carried out in STATA 14.1.11 case–control studies that consisted of 5730 cases and 6756 controls, were eventually included in our meta-analysis. The significant association was observed between the XPFrs2276466 polymorphism and neurogenic cancer susceptibility (recessive model: OR = 1.648, 95% CI = 1.294–2.098, P<0.001). Furthermore, no significant impact of this polymorphism was detected on decreased gastrointestinal cancer risk (dominant model: OR = 1.064, 95%CI = 0.961–1.177, P = 0.233). The rs2276466 polymorphism might play different roles in carcinogenesis of various cancer types. Current evidence did not suggest that this polymorphism was directly associated with gastrointestinal susceptibility. However, this polymorphism might contribute to increased neurogenic cancer risk. More preclinical and epidemiological studies are still imperative for further evaluation

Correlation of xeroderma pigmentosum complementation group F expression with gastric cancer and prognosis.

Correlation of xeroderma pigmentosum complementation group F (XPF) expression with gastric cancer and prognosis was investigated. We randomly selected 76 gastric cancer patients who were admitted to the Second People's Hospital of Dezhou City and received treatment, and detected XPF expression in gastric cancer tissues (observation group) and normal gastric mucosa adjacent to tumor (control group) via immunohistochemistry. Correlation between XPF expression and clinicopathological indicators of gastric cancer was verified via single-factor Chi-square test. Cox's proportional hazard regression model was used in the analysis of influencing factors of patient's prognosis, and Kaplan-Meier was used to analyze the survival rates of XPF-positive and -negative patients. In the observation group, the XPF-positive rate was significantly higher than that in the control group with a statistically significant difference (P<0.05). Single-factor analysis showed that XPF expression was correlated with the family history and Laurén classification (P<0.05). Kaplan-Meier survival analysis revealed that the survival time of XPF-positive patients was shorter than that of XPF-negative patients (P<0.05). Multifactorial analysis using Cox's hazards model suggested that XPF was an independent factor affecting the prognosis of gastric cancer (P<0.05). In conclusion, XPF expression plays an important role in the occurrence and development of gastric cancer, and a high expression of XPF suggests a poor prognosis of gastric cancer patients.

Neurodegeneration as the presenting symptom in 2 adults with xeroderma pigmentosum complementation group F.

ObjectiveTo describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting.MethodsWe report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F.ResultsBoth patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in ERCC4 and confirmed deficient NER capacity in skin fibroblasts from both patients.ConclusionsThese cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressive neurodegeneration accompanied by global brain atrophy and a history of heightened sun sensitivity, excessive freckling, and skin malignancies.

The age-related expression decline of ERCC1 and XPF for forensic age estimation: A preliminary study

The age-related capacity decline of DNA damage repair in human peripheral blood has been demonstrated. Excision repair cross-complementation group1 (ERCC1) and Xeroderma pigmentosum complementation group F (XPF) were rate-limiting enzyme in nucleotide excision repair (NER) which was known as the most important DNA damage repair system. Consequently, we hypothesized that the expression and/or activity of ERCC1 and XPF may be associated with age. However, little was known about the quantitative relationship of ERCC1 and XPF expression levels with age. The aim of the present study was to analyze the correlation of ERCC1 and XPF expression levels with age by detecting the ERCC1 and XPF mRNA levels in peripheral blood mononuclear cells(PBMCs) and protein levels in plasma in healthy ethnic Han Chinese individuals, and finally find new molecular markers for forensic age estimation by establishing the mathematical model between ERCC1 and XPF expression levels and age. The results showed that the ERCC1 and XPF mRNA relative expression levels in PBMCs declined in an age-dependent manner (r = −0.578/−0.844, respectively, P < 0.01). The formula for age estimation based on the ERCC1 and XPF mRNA relative expression levels decline in PBMCs were Y = 3.3E−5x2−0.0261x+1.9175 (R2 = 0.3244, P < 0.01) and Y = 0.0003x2−0.0459x+2.0439 (R2 = 0.729, P < 0.01), respectively. There were no significant differences of the ERCC1 or XPF protein expression levels in plasma between age groups (P > 0.05). Furthermore, there were no significant differences of the ERCC1 or XPF mRNA and/or protein expression levels between males and females(P > 0.05). It suggested that the ERCC1 and XPF mRNA expression levels could be considered as valuable additional tool in individual age estimation, especially in cases where traditional morphologic method was inefficient or absent in forensic practice.

Abstract PL05-01: ERCC1 alternative readouts

Abstract Platinum-based compounds, including cisplatin and oxaliplatin, trigger cell death by distorting the helix structure and subsequently affecting DNA replication and transcription. The therapeutic efficacy of platinum-based chemotherapy varies among patients and only a portion of them have real benefits. Precision medicine searches for the optimal therapy for each patient. The proteins involved in DNA repair are thus potential biomarkers to select patients more prone to respond to platinum-based chemotherapy. The ERCC1 (excision repair cross-complementation group 1) protein is essential in nucleotide excision repair (NER) and other repair pathways involved in the repair of platinum-induced DNA damages. ERCC1 with its partner XPF (xeroderma pigmentosum complementation group F) form a structure-specific endonuclease that is responsible for 5' incision during DNA repair. ERCC1 has been reported to be a prognostic and predictive biomarker for cisplatin treatments in various cancers. Many studies have shown that the ERCC1 status, including ERCC1 polymorphisms, ERCC1 RNA expression and ERCC1 protein expression, are associated with platinum-based therapy efficacy. However, this correlation between ERCC1 status and the clinical outcome has not always reached a consensus, probably due to inadequate methods to determine ERCC1 expression and unreliability of the current commercial ERCC1 antibodies. Alternative splicing leads to several isoforms of ERCC1. We have reported that only ERCC1-202 mediates highly efficient removal of platinum-GG intrastrand adducts and should therefore be considered as the only functional isoform. Putative roles of the other isoforms remain unknown. The expression of ERCC1 is mostly determined by qRT-PCR or IHC. However, these two methods are not able to discriminate the functional ERCC1-202 isoform from other isoforms. We will present the design of a tailor-made antibody directed against the interacting complex ERCC1/XPF. This new ERCC1/XPF heterodimer-specific antibody permits the detection of the functional ERCC1-202 isoform when it is used in combination with other antibodies in proximity ligation assays (PLA). The applicability of this alternative read out for ERCC1 expression on clinical samples will be discussed. Citation Format: Mei-Shiue Kuo, Ken A. Olaussen, Jean-Charles Soria. ERCC1 alternative readouts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL05-01.

The Cerebro-oculo-facio-skeletal Syndrome Point Mutation F231L in the ERCC1 DNA Repair Protein Causes Dissociation of the ERCC1-XPF Complex

The ERCC1-XPF heterodimer, a structure-specific DNA endonuclease, is best known for its function in the nucleotide excision repair (NER) pathway. The ERCC1 point mutation F231L, located at the hydrophobic interaction interface of ERCC1 (excision repair cross-complementation group 1) and XPF (xeroderma pigmentosum complementation group F), leads to severe NER pathway deficiencies. Here, we analyze biophysical properties and report the NMR structure of the complex of the C-terminal tandem helix-hairpin-helix domains of ERCC1-XPF that contains this mutation. The structures of wild type and the F231L mutant are very similar. The F231L mutation results in only a small disturbance of the ERCC1-XPF interface, where, in contrast to Phe(231), Leu(231) lacks interactions stabilizing the ERCC1-XPF complex. One of the two anchor points is severely distorted, and this results in a more dynamic complex, causing reduced stability and an increased dissociation rate of the mutant complex as compared with wild type. These data provide a biophysical explanation for the severe NER deficiencies caused by this mutation.

Association of single nucleotide polymorphisms of ERCC1 and XPF with colorectal cancer risk and interaction with tobacco use.

We investigated the association between polymorphisms in excision repair cross-complementation group 1 (ERCC1) (rs3212986, rs2298881 and rs11615) and xeroderma pigmentosum-complementation group F (XPF) (rs2276466 and rs6498486) and risk of colorectal cancer. A 1:1 matched case-control study was conducted. Conditional regression analysis indicated that individuals carrying the ERCC1 rs3212986 TT genotype and T allele had a marginally increased risk of colorectal cancer when compared with subjects with the GG genotype. Similarly, subjects carrying the rs11615 TT genotype and T allele had a marginally increased risk of colorectal cancer when compared with those with the CC genotype. Stratified analysis revealed that individuals with rs3212986 TT who were current or former smokers had a significantly increased risk of colorectal cancer, and a significant interaction was found between this SNP and cigarette smoking. In conclusion, our study suggests that rs3212986 and rs11615 polymorphisms are associated with risk of colorectal cancer in a Chinese population, particularly in smokers. This finding could be useful in revealing the genetic characteristics of colorectal cancer, and suggests more effective strategies for prevention and treatment.

Association of DNA repair gene polymorphisms with response to chemotherapy and prognosis of gastric cancer in a Chinese population.

We conducted a study to investigate the role of excision repair cross-complimentary group 1 gene (ERCC1)-xeroderma pigmentosum complementation group F (XPF) gene polymorphisms in response to chemotherapy and clinical outcome of gastric patients. Three SNPs in ERCC1 (rs11615, rs3212986, and rs2298881) and two SNPs in XPF (rs2276465 and rs6498486) were extracted using Tiangen DNA kit (Tiangen Biotech, Beijing, China) according to the manufacturer's instructions. The median follow-up time was 36.4 months, and ranged from 2-60 months. During the follow-up period, 112 patients died from gastric cancer. Individuals carrying ERCC1 rs11615 AA and XPF rs6498486 CC genotypes were associated with poorer response to chemotherapy when compared with wild-type genotype, with the ORs (95 % CI) of 0.48 (0.25-0.94) and 0.38 (0.14-1.00). In the Cox proportional hazards model, individuals carrying ERCC1 rs11615 GA and AA genotype had 1.91 and 2.66 risk of death when compared with those carrying GG genotype. Patients carrying the XPF rs6498486 AC and CC genotype were associate with 2.17 and 4.91-fold risk of death when compared with wild-type genotype. In conclusion, we found that ERCC1 rs11615 and XPF rs2276465 may substantially contribute to the future design of individualized cancer treatment in gastric cancer patients.

A nonsense mutation in the Xeroderma pigmentosum complementation group F (XPF) gene is associated with gastric carcinogenesis

XPF/ERCC1 endonuclease is required for DNA lesion repair. To assess effects of a C2169A nonsense mutation in XPF at position 2169 in gastric cancer tissues and cell lines, genomic DNA was extracted from blood samples of 488 cancer patients and 64 gastric tumors. The mutation was mapped using a TaqMan MGB probe. In addition, gastric cancer cell lines were transfected with mutated XPF to explore XPF/ERCC1 interaction, XPF degradation, and DNA repair by a comet assay. The C2169A mutation was not detected in 488 samples of blood genomic DNA, yet was found in 32 of 64 gastric cancer tissue samples (50.0%), resulting in a 194C-terminal amino acid loss in XPF protein and lower expression. Laser micro-dissection confirmed that this point mutation was not present in surrounding normal tissues from the same patients. The truncated form of XPF (tXPF) impaired interaction with ERCC1, was rapidly degraded via ubiquitination, and resulted in reduced DNA repair. In gastric cancers, the mutation was monoallelic, indicating that XPF is a haplo-insufficient DNA repair gene. As the C2169A mutation is closely associated with gastric carcinogenesis in the Chinese population, our findings shine light on it as a therapeutic target for early diagnosis and treatment of gastric cancer.

Association of polymorphisms of the xeroderma pigmentosum complementation group F gene with increased glioma risk.

We aimed to investigate the role of 4 single nucleotide polymorphisms of the xeroderma pigmentosum complementation group F (XPF) gene (rs3136038, rs1799798, rs1800067, and rs2276466) in glioma, and the roles of gene-gene interactions in the risk of developing this type of cancer. We collected samples from 225 glioma cases and 262 controls and genotyped the rs3136038, rs1799798, rs1800067, and rs2276466 polymorphisms using a 384-well plate format with the Sequenom MassARRAY platform. Individuals carrying the rs1800067 GG genotype were more likely to have an increased risk of glioma when compared with carriers of the A/A genotype in a co-dominant model, with an odds ratio (OR) [95% confidence interval (CI)] of 2.85 (1.14-7.76). However, we did not find an association with increased risk of glioma for the polymorphisms rs3136038, rs1799798, and rs2276466 in XPF. The combination genotype of the rs1800067 G allele and the rs2276466 G allele was associated with a moderate risk of glioma (OR = 1.71, 95%CI = 1.02-2.87). Our study suggests that the rs1800067 genetic variant of XPF functions in the development of glioma.

Polymorphisms in the ERCC1 and XPF genes and risk of breast cancer in a Chinese population.

Inherited functional single-nucleotide polymorphisms (SNPs) in DNA repair genes may influence the capability of DNA repair and contribute to the risk of breast cancer. We therefore performed a case-control study to investigate the association of three in excision repair cross-complimentary group 1 (ERCC1) and three in xeroderma pigmentosum complementation group F (XPF) with the risk of breast cancer. Genotyping of ERCC1 (rs2298881, rs3212986, and rs11615) and XPF (rs2276465, rs6498486, and rs2276466) was performed in a 384-well plate format on the MassARRAY(®) platform. Odds ratios and their corresponding 95% confidence intervals were used to assess the effect of each SNP on breast cancer risk. The ERCC1 rs11615 variant A/A genotype was associated with increased breast cancer risk in codominant, dominant, and recessive models, and XPF rs6498486 variant C/C genotype carriers have a significantly increased breast cancer risk in codominant, dominant, and recessive models. Individuals with both the ERCC1 rs11615 A allele and XPF rs6498486 C allele had a heavy increased risk of breast cancer compared to double wild-type homozygotes. The present study shows that the ERCC1 rs11615 and XPF rs6498486 polymorphisms are associated with breast cancer risk in a Chinese population. Further large-scale studies are required to elucidate whether these ERCC1 and XPF SNPs interact with environmental factors in the development of breast cancer.

Effects of polymorphisms in nucleotide excision repair genes on glioma risk in a Chinese population

We performed a case-control study to assess the relationship between six single nucleotide polymorphisms (SNPs) of xeroderma pigmentosum complementation group F (XPF) on glioma risk in a Chinese population. The six SNPs were genotyped in 330 glioma cases and 652 cancer-free controls using a 384-well plate format on the Sequenom MassARRAY platform (Sequenom, San Diego, USA). Rs1800067 did not follow the Hardy–Weinberg equilibrium in the control group, and the genotype distributions differed significantly between the two groups for SNPs rs1800067 and rs2276466. For rs1800067, the variant genotype T/T was strongly associated with an increased risk of glioma when compared with the A/A genotype (OR=3.77, 95% CI=2.38–6.01). Individuals with the rs1800067 G allele had a relatively high risk of glioma in a dominant model (OR=3.47, 95% CI=2.26–5.37). The rs2276466 G/G genotype was significantly associated with a moderate increased risk of glioma (OR=1.82, 95% CI=1.10–3.02) in a codominant model, and variation of rs25489 was associated with a 1.31- and 1.78-fold glioma risk in dominant and recessive models, respectively. Our study is the first to identify polymorphisms in rs1800067 and rs2276466 as correlated with glioma susceptibility.

Xeroderma Pigmentosum Complementation Group F Polymorphisms Influence Risk of Glioma

We conducted an exploratory investigation of whether variation in six common SNPs of xeroderma pigmentosum complementation group F (XPF) is associated with risk of glioma in a Chinese population. Six single nucleotide polymorphisms (SNPs) were genotyped in 207 glioma cases and 236 cancer-free controls by a 384-well plate format on the Sequenom MassARRAY platform (Sequenom, San Diego, USA). The rs1800067 G and rs2276466 G allele frequencies were significantly higher in the glioma group than controls. Individuals with the rs1800067 GG genotype were at greater risk of glioma when compared with the A/A genotype in the codominant model, with an OR (95% CI) of 2.63 (1.04-7.25). The rs2276466 polymorphism was significantly associated with moderate increased risk of glioma in codominant and dominant models, with ORs (95% CI) of 1.90 (1.05-3.44) and 1.55 (1.07-2.47), respectively. The combination genotype of rs1800067 G and rs2276466 G alleles was associated with a reduced risk of glioma (OR=0.44, 95% CI=0.19-0.98). These findings indicate that genetic variants of the XPF gene have critical functions in the development of glioma.

Effect of Xeroderma pigmentosum complementationgroup F polymorphisms and H.pylori infection on the risk of gastric cancer

We conducted a case-control study by genotyping three potential functional SNPs to assess the association of Xeroderma pigmentosum complementation group F (XPF) polymorphisms with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in the risk of gastric cancer. A hospital case-control study was conducted. A total of 331 patients with gastric cancer and 355 controls were collected. Three SNPs of XPF, XPF rs180067, rs1799801 and rs2276466, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find the significant difference in the genotype distributions of XPF rs180067, rs1799801 and rs2276466 between cases and controls. Multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. The stratification by H.pylori infection was not significantly different in polymorphisms of XPF rs180067, rs1799801 and rs2276466. There was no evidence that polymorphisms in rs180067, rs1799801 and rs2276466 significantly affect the risk of gastric cancer. Further large sample size studies are strongly needed to validate their association.

Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

Effect of Xeroderma Pigmentosum Complementation Group F Polymorphisms on Gastric Cancer Risk and Associations with H.pylori Infection

We conducted a hospital case-control study by genotyping four potential functional single nucleotide polymorphisms (SNPs) to assess the association of Xeroderma pigmentosum complementation group F (XPF) with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in risk definition. A total of 331 patients with gastric cancer and 355 controls were collected. Four SNPs of XPF, rs180067, rs1799801, rs2276466 and rs744154, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find any significant difference in the genotype distributions of XPF rs180067, rs1799801, rs2276466 and rs744154 between cases and controls. However, multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. A non-significant increased risk of gastric cancer was found in individuals carrying the rs744154 GG genotype. Stratification by H.pylori infection and smoking was not significantly different in polymorphisms of XPF rs180067, rs1799801, rs2276466 and rs744154. The four XPF SNPs did not show significant interaction with H.pylori infection and smoking status (P for interaction was 0.35 and 0.18, respectively). Our study indicated that polymorphisms in rs180067, rs1799801, rs2276466 and rs744154 may affect the risk of gastric cancer but further large sample size studies are needed to validate any association.

Control of genome stability by Slx protein complexes

The six Saccharomyces cerevisiae SLX genes were identified in a screen for factors required for the viability of cells lacking Sgs1, a member of the RecQ helicase family involved in processing stalled replisomes and in the maintenance of genome stability. The six SLX gene products form three distinct heterodimeric complexes, and all three have catalytic activity. Slx3-Slx2 (also known as Mus81-Mms4) and Slx1-Slx4 are both heterodimeric endonucleases with a marked specificity for branched replication fork-like DNA species, whereas Slx5-Slx8 is a SUMO (small ubiquitin-related modifier)-targeted E3 ubiquitin ligase. All three complexes play important, but distinct, roles in different aspects of the cellular response to DNA damage and perturbed DNA replication. Slx4 interacts physically not only with Slx1, but also with Rad1-Rad10 [XPF (xeroderma pigmentosum complementation group F)-ERCC1 (excision repair cross-complementing 1) in humans], another structure-specific endonuclease that participates in the repair of UV-induced DNA damage and in a subpathway of recombinational DNA DSB (double-strand break) repair. Curiously, Slx4 is essential for repair of DSBs by Rad1-Rad10, but is not required for repair of UV damage. Slx4 also promotes cellular resistance to DNA-alkylating agents that block the progression of replisomes during DNA replication, by facilitating the error-free mode of lesion bypass. This does not require Slx1 or Rad1-Rad10, and so Slx4 has several distinct roles in protecting genome stability. In the present article, I provide an overview of our current understanding of the cellular roles of the Slx proteins, paying particular attention to the advances that have been made in understanding the cellular roles of Slx4. In particular, protein-protein interactions and underlying molecular mechanisms are discussed and I draw attention to the many questions that have yet to be answered.

3058 POSTER Administration of reduced glutathione in FOLFOX4 regimen in advanced colorectal cancer: effect on oxaliplatin pharmacokinetics and on Pt-DNA adducts formation

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders—CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

A DNA repair gene of Caenorhabditis elegans: a homolog of human XPF

The xeroderma pigmentosum complementation group F (XPF) protein is a structure-specific endonuclease in a complex with ERCC1 and is essential for nucleotide excision repair (NER). We report a single cDNA of Caenorhabditis elegans ( C. elegans) encoding highly similar protein to human XPF and other XPF members. We propose to name the corresponding C. elegans gene xpf. Messenger RNA for C. elegans xpf is 5′-tagged with a SL2 splice leader, suggesting an operon-like expression for xpf. Using RNAi, we showed that loss of C. elegans xpf function caused hypersensitivity to ultra-violet (UV) irradiation, as observed in enhanced germ cell apoptosis and increased embryonic lethality. This study suggests that C. elegans xpf is conserved in evolution and plays a role in the repair of UV-damaged DNA in C. elegans.