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Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10151-6. doi: 10.1073/pnas.1610020113. Epub 2016 Aug 19.

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency.

Author information

1
Department of Pathology, University of Washington, Seattle, WA 98195;
2
Department of Dermatology, University of California, San Francisco, CA 94143;
3
California Pacific Medical Center, San Francisco, CA 94107.
4
Department of Dermatology, University of California, San Francisco, CA 94143; james.cleaver@ucsf.edu.

Abstract

Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are human photosensitive diseases with mutations in the nucleotide excision repair (NER) pathway, which repairs DNA damage from UV exposure. CS is mutated in the transcription-coupled repair (TCR) branch of the NER pathway and exhibits developmental and neurological pathologies. The XP-C group of XP patients have mutations in the global genome repair (GGR) branch of the NER pathway and have a very high incidence of UV-induced skin cancer. Cultured cells from both diseases have similar sensitivity to UV-induced cytotoxicity, but CS patients have never been reported to develop cancer, although they often exhibit photosensitivity. Because cancers are associated with increased mutations, especially when initiated by DNA damage, we examined UV-induced mutagenesis in both XP-C and CS cells, using duplex sequencing for high-sensitivity mutation detection. Duplex sequencing detects rare mutagenic events, independent of selection and in multiple loci, enabling examination of all mutations rather than just those that confer major changes to a specific protein. We found telomerase-positive normal and CS-B cells had increased background mutation frequencies that decreased upon irradiation, purging the population of subclonal variants. Primary XP-C cells had increased UV-induced mutation frequencies compared with normal cells, consistent with their GGR deficiency. CS cells, in contrast, had normal levels of mutagenesis despite their TCR deficiency. The lack of elevated UV-induced mutagenesis in CS cells reveals that their TCR deficiency, although increasing cytotoxicity, is not mutagenic. Therefore the absence of cancer in CS patients results from the absence of UV-induced mutagenesis rather than from enhanced lethality.

KEYWORDS:

RNA pol II; apoptosis; dipyrimidines; mutagenesis; transcription arrest

PMID:
27543334
PMCID:
PMC5018765
DOI:
10.1073/pnas.1610020113
[Indexed for MEDLINE]
Free PMC Article

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