DNA lesion identity drives choice of damage tolerance pathway in murine cell chromosomes

Isadora S. Cohen, Carmit Bar, Tamar Paz-Elizur, Elena Ainbinder, Karoline Leopold, Niels De Wind, Nicholas Geacintov, Zvi Livneh

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1637-1645
Number of pages9
JournalNucleic Acids Research
Volume43
Issue number3
DOIs
StatePublished - 2015

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Chromosomes
DNA Damage
DNA
Genomic Instability
Sunlight
Cell Lineage
Smoke
DNA Repair
Embryonic Structures
Fibroblasts
Genome
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Cohen, I. S., Bar, C., Paz-Elizur, T., Ainbinder, E., Leopold, K., De Wind, N., ... Livneh, Z. (2015). DNA lesion identity drives choice of damage tolerance pathway in murine cell chromosomes. Nucleic Acids Research, 43(3), 1637-1645. https://doi.org/10.1093/nar/gku1398

DNA lesion identity drives choice of damage tolerance pathway in murine cell chromosomes. / Cohen, Isadora S.; Bar, Carmit; Paz-Elizur, Tamar; Ainbinder, Elena; Leopold, Karoline; De Wind, Niels; Geacintov, Nicholas; Livneh, Zvi.

In: Nucleic Acids Research, Vol. 43, No. 3, 2015, p. 1637-1645.

Research output: Contribution to journalArticle

Cohen, IS, Bar, C, Paz-Elizur, T, Ainbinder, E, Leopold, K, De Wind, N, Geacintov, N & Livneh, Z 2015, 'DNA lesion identity drives choice of damage tolerance pathway in murine cell chromosomes', Nucleic Acids Research, vol. 43, no. 3, pp. 1637-1645. https://doi.org/10.1093/nar/gku1398
Cohen IS, Bar C, Paz-Elizur T, Ainbinder E, Leopold K, De Wind N et al. DNA lesion identity drives choice of damage tolerance pathway in murine cell chromosomes. Nucleic Acids Research. 2015;43(3):1637-1645. https://doi.org/10.1093/nar/gku1398
Cohen, Isadora S. ; Bar, Carmit ; Paz-Elizur, Tamar ; Ainbinder, Elena ; Leopold, Karoline ; De Wind, Niels ; Geacintov, Nicholas ; Livneh, Zvi. / DNA lesion identity drives choice of damage tolerance pathway in murine cell chromosomes. In: Nucleic Acids Research. 2015 ; Vol. 43, No. 3. pp. 1637-1645.
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