Nucleotide excision repair pathway gene polymorphisms are associated with risk and prognosis of colorectal cancer

BACKGROUND Single nucleotide polymorphisms(SNPs)are universally present in nucleotide excision repair(NER)pathway genes,which could make impacts on colorectal carcinogenesis and prognosis.AIM To explore the association of all tagSNPs in NER pathway genes with colorectal cancer(CRC)risk and prognosis in a northern Chinese population by a two-stage case-control design composed of a discovery and validation stage.METHODS Genotyping for NER SNPs was performed using kompetitive allele specific PCR.In the discovery stage,39 tagSNPs in eight genes were genotyped in 368 subjects,including 184 CRC cases and 184 individual-matched controls.In the validation stage,13 SNPs in six genes were analyzed in a total of 1712 subjects,including 854 CRC cases and 858 CRC-free controls.RESULTS Two SNPs(XPA rs10817938 and XPC rs2607775)were associated with an increased CRC risk in overall and stratification analyses.Significant cumulative and interaction effects were also demonstrated in the studied SNPs on CRC risk.Another two SNPs(ERCC2 rs1052555 and ERCC5 rs2228959)were newly found to be associated with a poor overall survival of CRC patients.CONCLUSION Our findings suggest novel SNPs in NER pathway genes that can be predictive for CRC risk and prognosis in a large-scale Chinese population.The present study has referential values for the identification of all-round NER-based genetic biomarkers in predicting the susceptibility and clinical outcome of CRC.

DNA Repair Gene Polymorphisms in the Nucleotide Excision Repair Pathway and Lung Cancer Risk: A Meta-analysis

Objective： A number of studies have reported the association of ＂XPA＂, ＂XPC＂, ＂XPD/ERCC2＂ gene polymorphisms with lung cancer risk. However, the results were conflict. To clarify the impact of polymorphisms of ＂XPA＂, ＂XPC＂, ＂XPD/ERCC2＂, on lung cancer risk, a meta-analysis was performed in this study. Methods： The electronic databases PubMed and Embase were retrieved for studies included in this meta-analysis by ＂XPA＂, ＂XPC＂, ＂XPD/ERCC2＂, ＂lung＂, ＂cancer/neoplasm/tumor/carcinoma＂, ＂polymorphism＂ （An upper date limit of October, 31, 2009）. A meta-analysis was performed to evaluate the relationship among XPA, XPC and XPD polymorphism and lung cancer risks. Results： A total of 31 publications retrieved from Pubmed and Embase included in this study. XPC A939C CC genotype increased lung cancer risk in total population （recessive genetic model： OR=1.23, 95% CI：1.05-1.44; homozygote comparison： OR=1.21,95%CI：1.02-1.43and CC vs. CA contrast： OR=1.25,95%CI：1.06-1.48）, except in Asians. XPD A751C, 751C allele and CC genotype also increased lung cancer risk in total population and in Caucasians （recessive genetic model： Total population： OR=1.20, 95%CI：1.07-1.35）. No significant correlation was found between XPD A751C and lung cancer risk in Asians and African Americans. XPD G312A AA genotype increased lung cancer risk in total population, in Asians and Caucasians（recessive genetic model： Total population： OR=1.20, 95%CI： 1.06-1.36）. No significant association was found between XPA G23A, XPC C499T, XPD C156A and lung cancer risk. Conclusion： Our results suggest that the polymorphisms in XPC and XPD involve in lung cancer risks. XPA polymorphisms is less related to lung cancer risk.

Diffusion of nucleotide excision repair protein XPA along DNA by coarse-grained molecular simulations

Protein XPA plays critical roles in nucleotide excision repair pathway.Recent experimental work showed that the functional dynamics of XPA involves the one-dimensional diffusion along DNA to search the damage site.Here,we investigate the involved dynamical process using extensive coarse-grained molecular simulations at various salt concentrations.The results demonstrated strong salt concentration dependence of the diffusion mechanisms.At low salt concentrations,the one-dimensional diffusion with rotational coupling is the dominant mechanism.At high salt concentrations,the diffusion by three-dimensional mechanism becomes more probable.At wide range of salt concentrations,the residues involved in the DNA binding are similar and the one-dimensional diffusion of XPA along DNA displays sub-diffusive feature.This sub-diffusive feature is tentatively attributed to diverse strengths of XPA-DNA interactions.In addition,we showed that both binding to DNA and increasing salt concentration tend to stretch the conformation of the XPA,which increases the exposure extent of the sites for the binding of other repair proteins.

Pharmacogenomics of Cisplatin Sensitivity in Non-small Cell Lung Cancer

Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer （NSCLC） as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomark- ers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensitivity biomarkers in NSCLC. We focused on several key pathways, including nucleotide excision repair, drug transport and metabolism. Both expression and germline DNA variation were evaluated in these key pathways. Current evidence suggests that cisplatin-based treatment could be improved by the use of these biomarkers.

Enhancing alkylating agent resistance through ERCC2 gene transfection in human glioma cell line

Objective To confirm the enhancing effect of excision repair cross complementing rodent repair deficiency gene 2 (ERCC2) on alkylating agents resistance. Methods The authors constructed a pcDNA3-ERCC2 plasmid. The pcDNA3-ERCC2 was transfected into a selected ERCC2 negative human glioma cell line,SKMG-4,using liposome-mediated transfection. After G418 selection,a stable transfected cell line was obtained and tested for cytotoxicity of several alkylating agents.Results The stable transfectant was obtained and confirmed by RT-PCR as well as Western blot analysis to be strongly expressing ERCC2 at both mRNA and protein levels. The IC 90 (μmol/L) of two alkylating agents,cisplatin and melphalan,increased from 1.0 to 1.75 (75%) and 5.6 to 9.0 (61%),respectively,compared with control cell line.Conclusion The present data provided evidences and confirmed the authors’ previous results that ERCC2 contributes,at least partially,to alkylating agent resistance in human glioma cell line.

How two helicases work together within the TFIIH complex, a perspective from structural studies of XPB and XPD helicases

Xeroderma pigmentosum group B （XPB） and D （XPD） are two DNA helicases inside the transcription factor TFIIH complex required for both transcription and DNA repair. The importance of these helicases is underscored by the fact that mutations of XPB and XPD cause diseases with extremely high sensitivity to UV-light and high risk of cancer, premature aging, etc. This mini-review focuses on recent developments in both structural and functional characterization of these XP heficases to illustrate their distinguished biological roles within the architectural restriction of the TFIIH complex. In particular, molecular mechanisms of DNA unwinding by these helicases for promoter opening during transcription initiation and bubble-creation around the lesion during DNA repair are described based on the integration of the crystal structures of XPB and XPD helicases into the architecture of the TFIIH complex.