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 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.
authors.affiliation: 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.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Zheng
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Sciences University, Portland, OR 97239, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wang
authors.affiliation: Emerging Technology Research Center, Samsung Advanced Institute of Technology, Kyunggi-do 446-712, Korea.
authors.forename: Jongsuk
authors.initials: J
authors.lastname: Chung
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Homayoun
authors.initials: H
authors.lastname: Moslehi
authors.affiliation: Five3 Genomics, LLC, Santa Cruz, CA 95060, USA.
authors.forename: J Zachary
authors.initials: JZ
authors.lastname: Sanborn
authors.affiliation: Headquarters, Samsung Electronics, Seocho-gu, Seoul 137-857, Korea.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Hur
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Swapna S
authors.initials: SS
authors.lastname: Vemula
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Agne
authors.initials: A
authors.lastname: Naujokas
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR 97239, USA.
authors.forename: Kami E
authors.initials: KE
authors.lastname: Chiotti
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Cheng
authors.affiliation: National Xeroderma Pigmentosum Service, St John's Institute of Dermatology, Guy's and St Thomas' NHS Trust, London SE1 9RT, UK.
authors.forename: Hiva
authors.initials: H
authors.lastname: Fassihi
authors.affiliation: Department of Mathematics, University of Texas, Austin, Austin, TX 78712, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Blumberg
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Celeste V
authors.initials: CV
authors.lastname: Bailey
authors.affiliation: Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Fudem
authors.affiliation: Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University Medical Center, Stanford, CA 94305, USA.
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Mihm
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Bari B
authors.initials: BB
authors.lastname: Cunningham
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Neuhaus
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Oh
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Cleaver
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: LeBoit
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RH, UK.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.affiliation: Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR 97239, USA; Department of Biomedical Engineering, Oregon Health & Sciences University, Portland, OR 97239, USA.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: 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.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Arron
authors.affiliation: Emerging Technology Research Center, Samsung Advanced Institute of Technology, Kyunggi-do 446-712, Korea.
authors.forename: Nam
authors.initials: N
authors.lastname: Huh
authors.affiliation: Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: epurdom@stat.berkeley.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Purdom
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: chorj@derm.ucsf.edu.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Cho
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D042003:DNA Packaging / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism; D006570:Heterochromatin / Q000235:genetics*; D006801:Humans; D059645:Mutation Rate; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D006570:Heterochromatin; D011518:Proto-Oncogene Proteins; C086984:XPC protein, human