Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

Christina L Zheng; Nicholas J Wang; Jongsuk Chung; Homayoun Moslehi; J Zachary Sanborn; Joseph S Hur; Eric A Collisson; Swapna S Vemula; Agne Naujokas; Kami E Chiotti; Jeffrey B Cheng; Hiva Fassihi; Andrew J Blumberg; Celeste V Bailey; Gary M Fudem; Frederick G Mihm; Bari B Cunningham; Isaac M Neuhaus; Wilson Liao; Dennis H Oh; James E Cleaver; Philip E LeBoit; Joseph F Costello; Alan R Lehmann; Joe W Gray; Paul T Spellman; Sarah T Arron; Nam Huh; Elizabeth Purdom; Raymond J Cho

doi:10.1016/j.celrep.2014.10.031

Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

Cell Rep. 2014 Nov 20;9(4):1228-34. doi: 10.1016/j.celrep.2014.10.031. Epub 2014 Nov 20.

Authors

Christina L Zheng¹, Nicholas J Wang², Jongsuk Chung³, Homayoun Moslehi⁴, J Zachary Sanborn⁵, Joseph S Hur⁶, Eric A Collisson⁷, Swapna S Vemula⁸, Agne Naujokas⁸, Kami E Chiotti⁹, Jeffrey B Cheng⁴, Hiva Fassihi¹⁰, Andrew J Blumberg¹¹, Celeste V Bailey¹², Gary M Fudem¹³, Frederick G Mihm¹⁴, Bari B Cunningham¹⁵, Isaac M Neuhaus⁴, Wilson Liao⁴, Dennis H Oh¹⁶, James E Cleaver⁴, Philip E LeBoit⁸, Joseph F Costello¹⁷, Alan R Lehmann¹⁸, Joe W Gray¹⁹, Paul T Spellman²⁰, Sarah T Arron⁴, Nam Huh³, Elizabeth Purdom²¹, Raymond J Cho²²

Affiliations

¹ Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Sciences University, Portland, OR 97239, USA; Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR 97239, USA.
² Department of Biomedical Engineering, Oregon Health & Sciences University, Portland, OR 97239, USA.
³ Emerging Technology Research Center, Samsung Advanced Institute of Technology, Kyunggi-do 446-712, Korea.
⁴ Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Five3 Genomics, LLC, Santa Cruz, CA 95060, USA.
⁶ Headquarters, Samsung Electronics, Seocho-gu, Seoul 137-857, Korea.
⁷ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR 97239, USA.
¹⁰ National Xeroderma Pigmentosum Service, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London SE1 9RT, UK.
¹¹ Department of Mathematics, University of Texas, Austin, Austin, TX 78712, USA.
¹² UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
¹³ Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, USA.
¹⁴ Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University Medical Center, Stanford, CA 94305, USA.
¹⁵ Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁶ Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Dermatology Research Unit, Veterans Affairs Medical Center, San Francisco, San Francisco, CA 94121, USA.
¹⁷ Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
¹⁸ Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RH, UK.
¹⁹ Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR 97239, USA; Department of Biomedical Engineering, Oregon Health & Sciences University, Portland, OR 97239, USA.
²⁰ Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR 97239, USA; Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR 97239, USA.
²¹ Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: [email protected].
²² Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].

Abstract

Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Squamous Cell / genetics*
DNA Packaging / genetics
DNA Repair / genetics*
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics
Gene Expression Regulation, Neoplastic
Genome, Human / genetics*
Germ Cells / metabolism
Heterochromatin / genetics*
Humans
Mutation Rate*
Proto-Oncogene Proteins / genetics
Skin Neoplasms / genetics*
Transcription, Genetic*

Substances

DNA-Binding Proteins
Heterochromatin
Proto-Oncogene Proteins
XPC protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding