Journal
CELL CYCLE
Volume 17, Issue 7, Pages 833-843Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2018.1456296
Keywords
DNA damage; trans-lesion synthesis (TLS); RAD18; mutagenesis; genome maintenance; cancer
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Funding
- Intramural Research Program of the National Library of Medicine at the National Institutes of Health
- Moravskoslezsky kraj research initiative [01211/2016/RRC]
- National Institutes of Health [R01 CA215347]
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Mutagenesis is a hallmark and enabling characteristic of cancer cells. The E3 ubiquitin ligase RAD18 and its downstream effectors, the Y-family' Trans-Lesion Synthesis (TLS) DNA polymerases, confer DNA damage tolerance at the expense of DNA replication fidelity. Thus, RAD18 and TLS polymerases are attractive candidate mediators of mutagenesis and carcinogenesis. The skin cancer-propensity disorder xeroderma pigmentosum-variant (XPV) is caused by defects in the Y-family DNA polymerase Pol eta (Pol). However it is unknown whether TLS dysfunction contributes more generally to other human cancers. Recent analyses of cancer genomes suggest that TLS polymerases generate many of the mutational signatures present in diverse cancers. Moreover biochemical studies suggest that the TLS pathway is often reprogrammed in cancer cells and that TLS facilitates tolerance of oncogene-induced DNA damage. Here we review recent evidence supporting widespread participation of RAD18 and the Y-family DNA polymerases in the different phases of multi-step carcinogenesis.
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