期刊
NUCLEIC ACIDS RESEARCH
卷 43, 期 3, 页码 1637-1645出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku1398
关键词
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资金
- Flight Attendant Medical Research Institute, Florida, USA
- Leona M. and Harry B. Helmsley Charitable Trust, NY, USA
- Israel Science Foundation [1136/08, 684/12]
- U.S. National Institutes of Health/National Cancer Institute [CA099194]
DNA-damage tolerance (DDT) via translesion DNA synthesis (TLS) or homology-dependent repair (HDR) functions to bypass DNA lesions encountered during replication, and is critical for maintaining genome stability. Here, we present piggyBlock, a new chromosomal assay that, using piggyBac transposition of DNA containing a known lesion, measures the division of labor between the two DDT pathways. We show that in the absence of DNA damage response, tolerance of the most common sunlight-induced DNA lesion, TT-CPD, is achieved by TLS in mouse embryo fibroblasts. Meanwhile, BP-G, a major smoke-induced DNA lesion, is bypassed primarily by HDR, providing the first evidence for this mechanism being the main tolerance pathway for a biologically important lesion in a mammalian genome. We also show that, far from being a last-resort strategy as it is sometimes portrayed, TLS operates alongside nucleotide excision repair, handling 40% of TT-CPDs in repair-proficient cells. Finally, DDT acts in mouse embryonic stem cells, exhibiting the same pattern-mutagenic TLS included-despite the risk of propagating mutations along all cell lineages. The new method highlights the importance of HDR, and provides an effective tool for studying DDT in mammalian cells.
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