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. OhJames 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

Research output: Contribution to journalArticle

49 Scopus citations

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 primarycause 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.

Original languageEnglish (US)
Pages (from-to)1228-1234
Number of pages7
JournalCell Reports
Volume9
Issue number4
DOIs
StatePublished - Nov 20 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Transcription Restores DNA Repair to Heterochromatin, Determining Regional Mutation Rates in Cancer Genomes'. Together they form a unique fingerprint.

  • Cite this

    Zheng, C. L., Wang, N. J., Chung, J., Moslehi, H., Sanborn, J. Z., Hur, J. S., Collisson, E. A., Vemula, S. S., Naujokas, A., Chiotti, K. E., Cheng, J. B., Fassihi, H., Blumberg, A. J., Bailey, C. V., Fudem, G. M., Mihm, F. G., Cunningham, B. B., Neuhaus, I. M., Liao, W., ... Cho, R. J. (2014). Transcription Restores DNA Repair to Heterochromatin, Determining Regional Mutation Rates in Cancer Genomes. Cell Reports, 9(4), 1228-1234. https://doi.org/10.1016/j.celrep.2014.10.031