UMMS Affiliation

Department of Surgery

Date

11-20-2014

Document Type

Article

Subjects

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

Disciplines

Bioinformatics | Cancer Biology | Computational Biology | Genetics | Genomics | Neoplasms

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.

Rights and Permissions

Citation: Cell Rep. 2014 Nov 20;9(4):1228-34. doi: 10.1016/j.celrep.2014.10.031. Epub 2014 Nov 20. Link to article on publisher's site.

DOI of Published Version

10.1016/j.celrep.2014.10.031

Comments

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

Journal Title

Cell reports

PubMed ID

25456125

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

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