@article{b80d102f13c04b44ba0c18ca2c2a4b9c,
title = "Transcription Restores DNA Repair to Heterochromatin, Determining Regional Mutation Rates in Cancer Genomes",
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.",
author = "Zheng, {Christina L.} and Wang, {Nicholas J.} and Jongsuk Chung and Homayoun Moslehi and Sanborn, {J. Zachary} and Hur, {Joseph S.} and Collisson, {Eric A.} and Vemula, {Swapna S.} and Agne Naujokas and Chiotti, {Kami E.} and Cheng, {Jeffrey B.} and Hiva Fassihi and Blumberg, {Andrew J.} and Bailey, {Celeste V.} and Fudem, {Gary M.} and Mihm, {Frederick G.} and Cunningham, {Bari B.} and Neuhaus, {Isaac M.} and Wilson Liao and Oh, {Dennis H.} and Cleaver, {James E.} and LeBoit, {Philip E.} and Costello, {Joseph F.} and Lehmann, {Alan R.} and Gray, {Joe W.} and Spellman, {Paul T.} and Arron, {Sarah T.} and Nam Huh and Elizabeth Purdom and Cho, {Raymond J.}",
note = "Funding Information: We thank Peggy Tuttle and Maria Damen for help in sample procurement and Dr. Leslie Cope for manuscript comments. This work was supported by the Well Aging Research Center, Samsung Advanced Institute of Technology, under the auspices of Professor Sang Chul Park, the Dermatology Foundation, NIH, National Cancer Institute grants K08 CA169865 (R.J.C.) and U54 CA112970 and by the OHSU Knight Cancer Institute (J.W.G.). We appreciate assistance with artwork from Sarah Pyle and Eli Blair Media. Publisher Copyright: {\textcopyright} 2014 The Authors.",
year = "2014",
month = nov,
day = "20",
doi = "10.1016/j.celrep.2014.10.031",
language = "English (US)",
volume = "9",
pages = "1228--1234",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}