Nucleotide excision repair is impaired by binding of transcription factors to DNA

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

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Accelerated accumulation of somatic mutations in mice deficient in the nucleotide excision repair gene XPA

Oncogene ◽

10.1038/sj.onc.1202404 ◽

1999 ◽

Vol 18 (5) ◽

pp. 1257-1260 ◽

Cited By ~ 26

Author(s):

Heidi Giese ◽

Martijn ET Dollé ◽

Aram Hezel ◽

Harry van Steeg ◽

Jan Vijg

Keyword(s):

Nucleotide Excision Repair ◽

Somatic Mutations ◽

Excision Repair ◽

Repair Gene ◽

Nucleotide Excision Repair Gene ◽

Nucleotide Excision

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Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial

Cancers ◽

10.3390/cancers12071742 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1742

Author(s):

Mitsukuni Suenaga ◽

Marta Schirripa ◽

Shu Cao ◽

Wu Zhang ◽

Dongyun Yang ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Nucleotide Excision Repair ◽

Binding Sites ◽

Excision Repair ◽

Dependent Manner ◽

Nucleotide Polymorphisms ◽

Wild Type ◽

First Line ◽

Single Nucleotide ◽

Nucleotide Excision

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07–5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27–6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09–0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56–1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. Conclusion: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV.

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ABF1-binding Sites Promote Efficient Global Genome Nucleotide Excision Repair

Journal of Biological Chemistry ◽

10.1074/jbc.m806830200 ◽

2008 ◽

Vol 284 (2) ◽

pp. 966-973 ◽

Cited By ~ 17

Author(s):

Shirong Yu ◽

Julia B. Smirnova ◽

Errol C. Friedberg ◽

Bruce Stillman ◽

Masahiro Akiyama ◽

...

Keyword(s):

Nucleotide Excision Repair ◽

Binding Sites ◽

Excision Repair ◽

Nucleotide Excision

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CpG methylation accounts for genome-wide C>T mutation variation and cancer driver formation across cancer types

10.1101/106872 ◽

2017 ◽

Author(s):

Rebecca C. Poulos ◽

Jake Olivier ◽

Jason W. H. Wong

Keyword(s):

Cytosine Methylation ◽

Excision Repair ◽

Replication Timing ◽

Cpg Methylation ◽

Tissue Type ◽

Driver Mutations ◽

Cancer Subtypes ◽

Cancer Driver ◽

Timing Data ◽

Cancer Types

AbstractCytosine methylation (5mC) is vital for cellular function, and yet 5mC sites are also commonly mutated in the genome. In this study, we analyse the genomes of over 900 cancer samples, together with tissue type-specific methylation and replication timing data. We describe a strong mutation-methylation association in colorectal cancers with microsatellite instability (MSI) or withPolymerase epsilon (POLE)exonuclease domain mutation. We describe a potential role for mismatch repair in the correction of mismatches resulting from deamination of 5mC, and propose a mutator phenotype to exist inPOLE-mutant cancers specifically at 5mC sites. We also associatePOLE-mutant hotspot coding mutations inAPCandTP53with CpG methylation. Analysing mutations across additional cancer types, we identify nucleotide excision repair- and AID/APOBEC-induced processes to underlie differential mutation-methylation associations in certain cancer subtypes. This study reveals differential associations vital for accurately mapping regional variation in mutation density and pinpointing driver mutations in cancer.

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