Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer

Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Mutational characteristics of NER-deficiency may reveal important diagnostic opportunities, as tumors deficient in NER are more sensitive to certain treatments. Here, we analyzed the genome-wide somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Ercc1−/Δ mice. Our results indicate that NER-deficiency increases the base substitution load twofold in liver but not in small intestinal ASCs, which coincides with the tissue-specific aging pathology observed in these mice. Moreover, NER-deficient ASCs of both tissues show an increased contribution of Signature 8 mutations, which is a mutational pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the base substitutions indicates that deficiency of global-genome NER (GG-NER) underlies the observed mutational consequences. In line with this, we observe increased Signature 8 mutations in a GG-NER-deficient human organoid culture, in which XPC was deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations could therefore contribute to a predictor of NER-deficiency based on a patient's mutational profile.

[1]  Ville Mustonen,et al.  The repertoire of mutational signatures in human cancer , 2018, Nature.

[2]  S. Nik-Zainal,et al.  Validating the concept of mutational signatures with isogenic cell models , 2018, Nature Communications.

[3]  Peter J. Park,et al.  Aging and neurodegeneration are associated with increased mutations in single human neurons , 2017, Science.

[4]  E. Cuppen,et al.  Measuring mutation accumulation in single human adult stem cells by whole-genome sequencing of organoid cultures , 2017, Nature Protocols.

[5]  Edwin Cuppen,et al.  MutationalPatterns: comprehensive genome-wide analysis of mutational processes , 2016, Genome Medicine.

[6]  S. Nik-Zainal,et al.  Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer , 2017, Science.

[7]  Swe Swe Myint,et al.  Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors , 2017, bioRxiv.

[8]  E. Birney,et al.  HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures , 2017, Nature Medicine.

[9]  Hans Clevers,et al.  Tissue-specific mutation accumulation in human adult stem cells during life , 2016, Nature.

[10]  D. Ellison,et al.  Multi-organ Mapping of Cancer Risk , 2016, Cell.

[11]  J. Pennings,et al.  Diet restriction delays accelerated aging and genomic stress in DNA repair deficient mice , 2016, Nature.

[12]  David C. Jones,et al.  Landscape of somatic mutations in 560 breast cancer whole genome sequences , 2016, Nature.

[13]  Anushi Shah,et al.  Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes , 2016, Nature.

[14]  Gad Getz,et al.  Somatic ERCC2 Mutations Are Associated with a Distinct Genomic Signature in Urothelial Tumors , 2016, Nature Genetics.

[15]  E. Cuppen,et al.  Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure , 2016, Scientific Reports.

[16]  M. Stratton,et al.  Clock-like mutational processes in human somatic cells , 2015, Nature Genetics.

[17]  H. Naegeli,et al.  Xeroderma pigmentosum group C sensor: unprecedented recognition strategy and tight spatiotemporal regulation , 2015, Cellular and Molecular Life Sciences.

[18]  K. Rudolph,et al.  Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer , 2015, Cell stem cell.

[19]  A. Dupuy,et al.  DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease. , 2015, Mutation research.

[20]  Frances M. G. Pearl,et al.  Therapeutic opportunities within the DNA damage response , 2015, Nature Reviews Cancer.

[21]  J. Kench,et al.  Whole genomes redefine the mutational landscape of pancreatic cancer , 2015, Nature.

[22]  Hans Clevers,et al.  Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver , 2015, Cell.

[23]  Nam Huh,et al.  Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes. , 2014, Cell reports.

[24]  Asif U. Tamuri,et al.  Genome sequencing of normal cells reveals developmental lineages and mutational processes , 2014, Nature.

[25]  J. Hoeijmakers,et al.  Understanding nucleotide excision repair and its roles in cancer and ageing , 2014, Nature Reviews Molecular Cell Biology.

[26]  Jin-rong Qiu,et al.  Association of ERCC1 and ERCC2 polymorphisms with colorectal cancer risk in a Chinese population , 2014, Scientific Reports.

[27]  Mauricio O. Carneiro,et al.  From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline , 2013, Current protocols in bioinformatics.

[28]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[29]  D. Gordenin,et al.  Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines , 2013, Nucleic acids research.

[30]  David M. Wilson,et al.  DNA repair mechanisms in dividing and non-dividing cells. , 2013, DNA repair.

[31]  J. Cadet,et al.  Oxidatively generated complex DNA damage: tandem and clustered lesions. , 2012, Cancer letters.

[32]  Thomas Zichner,et al.  DELLY: structural variant discovery by integrated paired-end and split-read analysis , 2012, Bioinform..

[33]  B. Schuster-Böckler,et al.  Chromatin organization is a major influence on regional mutation rates in human cancer cells , 2012, Nature.

[34]  Advaitha Madireddy,et al.  Multiple DNA Binding Domains Mediate the Function of the ERCC1-XPF Protein in Nucleotide Excision Repair* , 2012, The Journal of Biological Chemistry.

[35]  G. Michalopoulos,et al.  A mouse model of accelerated liver aging caused by a defect in DNA repair , 2012, Hepatology.

[36]  Tatiana Popova,et al.  Supplementary Methods , 2012, Acta Neuropsychiatrica.

[37]  J. Hoeijmakers,et al.  Broad segmental progeroid changes in short-lived Ercc1−/Δ7 mice , 2011, Pathobiology of aging & age related diseases.

[38]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[39]  K. Kirschner,et al.  Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. , 2010, Anticancer research.

[40]  J. Rahn,et al.  Multiple roles of ERCC1‐XPF in mammalian interstrand crosslink repair , 2010, Environmental and molecular mutagenesis.

[41]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[42]  J. Pablo Radicella,et al.  HO• radicals induce an unexpected high proportion of tandem base lesions refractory to repair by DNA glycosylases , 2010, Proceedings of the National Academy of Sciences.

[43]  Tom Royce,et al.  A comprehensive catalogue of somatic mutations from a human cancer genome , 2010, Nature.

[44]  J. Hoeijmakers.  DNA damage, aging, and cancer. , 2009, The New England journal of medicine.

[45]  E. Birney,et al.  Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt , 2009, Nature Protocols.

[46]  H. Clevers,et al.  Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche , 2009, Nature.

[47]  Hans Clevers,et al.  Crypt stem cells as the cells-of-origin of intestinal cancer , 2009, Nature.

[48]  H. Moon,et al.  Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes. , 2008, Cancer research.

[49]  T. Helleday,et al.  The ERCC1/XPF endonuclease is required for efficient single-strand annealing and gene conversion in mammalian cells , 2007, Nucleic acids research.

[50]  J. Hoeijmakers,et al.  A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis , 2006, Nature.

[51]  C. Peschle,et al.  Identification of a molecular signature for leukemic promyelocytes and their normal counterparts: focus on DNA repair genes , 2006, Leukemia.

[52]  J. Hoeijmakers,et al.  Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. , 2006, Mutation research.

[53]  R. Kaptein,et al.  The structure of the human ERCC1/XPF interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. , 2005, Structure.

[54]  Bart De Moor,et al.  BioMart and Bioconductor: a powerful link between biological databases and microarray data analysis , 2005, Bioinform..

[55]  Doree Sitkoff,et al.  models homology modeling : From sequence alignments to structural A comparative study of available software for high-accuracy , 2005 .

[56]  G. Pfeifer,et al.  Oxidative DNA damage induced by copper and hydrogen peroxide promotes CG-->TT tandem mutations at methylated CpG dinucleotides in nucleotide excision repair-deficient cells. , 2002, Nucleic acids research.

[57]  W. de Laat,et al.  Mapping of interaction domains between human repair proteins ERCC1 and XPF. , 1998, Nucleic acids research.

[58]  H. Morreau,et al.  Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence , 1997, Current Biology.

[59]  R. Wood,et al.  Xeroderma Pigmentosum Group F Caused by a Defect in a Structure-Specific DNA Repair Endonuclease , 1996, Cell.

[60]  P. J. van der Spek,et al.  Mutational analysis of the human nucleotide excision repair gene ERCC1. , 1996, Nucleic acids research.

[61]  A. Bradley,et al.  High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC , 1995, Nature.

[62]  E. Ohtsuka,et al.  8-Hydroxyguanine (7,8-dihydro-8-oxoguanine) in hot spots of the c-Ha-ras gene: effects of sequence contexts on mutation spectra. , 1995, Carcinogenesis.

[63]  R. Wood,et al.  Mammalian DNA nucleotide excision repair reconstituted with purified protein components , 1995, Cell.

[64]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .