Cell Reports (Nov 2014)
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
Affiliations
- Christina L. Zheng
- Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Sciences University, Portland, OR 97239, USA
- Nicholas J. Wang
- Department of Biomedical Engineering, Oregon Health & Sciences University, Portland, OR 97239, USA
- Jongsuk Chung
- Emerging Technology Research Center, Samsung Advanced Institute of Technology, Kyunggi-do 446-712, Korea
- Homayoun Moslehi
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- J. Zachary Sanborn
- Five3 Genomics, LLC, Santa Cruz, CA 95060, USA
- Joseph S. Hur
- Headquarters, Samsung Electronics, Seocho-gu, Seoul 137-857, Korea
- Eric A. Collisson
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Swapna S. Vemula
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
- Agne Naujokas
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
- Kami E. Chiotti
- Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR 97239, USA
- Jeffrey B. Cheng
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- Hiva Fassihi
- National Xeroderma Pigmentosum Service, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Trust, London SE1 9RT, UK
- Andrew J. Blumberg
- Department of Mathematics, University of Texas, Austin, Austin, TX 78712, USA
- Celeste V. Bailey
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
- Gary M. Fudem
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, USA
- Frederick G. Mihm
- Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University Medical Center, Stanford, CA 94305, USA
- Bari B. Cunningham
- Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
- Isaac M. Neuhaus
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- Wilson Liao
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- Dennis H. Oh
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- James E. Cleaver
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- Philip E. LeBoit
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
- Joseph F. Costello
- Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA
- Alan R. Lehmann
- Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RH, UK
- Joe W. Gray
- Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR 97239, USA
- Paul T. Spellman
- Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR 97239, USA
- Sarah T. Arron
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- Nam Huh
- Emerging Technology Research Center, Samsung Advanced Institute of Technology, Kyunggi-do 446-712, Korea
- Elizabeth Purdom
- Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA
- Raymond J. Cho
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
- DOI
- https://doi.org/10.1016/j.celrep.2014.10.031
- Journal volume & issue
-
Vol. 9,
no. 4
pp. 1228 – 1234
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.
