Journal
EMBO REPORTS
Volume 20, Issue 9, Pages -Publisher
WILEY
DOI: 10.15252/embr.201847250
Keywords
ATM; ATR; DNA damage response; post-replicative repair; R loop
Categories
Funding
- European Research Council [ERC2014 AdG669898 TARLOOP]
- Worldwide Cancer Research [WCR15-00098]
- WCR
- Scientific Foundation of the Spanish Association Against Cancer (AECC)
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Despite playing physiological roles in specific situations, DNA-RNA hybrids threat genome integrity. To investigate how cells do counteract spontaneous DNA-RNA hybrids, here we screen an siRNA library covering 240 human DNA damage response (DDR) genes and select siRNAs causing DNA-RNA hybrid accumulation and a significant increase in hybrid-dependent DNA breakage. We identify post-replicative repair and DNA damage checkpoint factors, including those of the ATM/CHK2 and ATR/CHK1 pathways. Thus, spontaneous DNA-RNA hybrids are likely a major source of replication stress, but they can also accumulate and menace genome integrity as a consequence of unrepaired DSBs and post-replicative ssDNA gaps in normal cells. We show that DNA-RNA hybrid accumulation correlates with increased DNA damage and chromatin compaction marks. Our results suggest that different mechanisms can lead to DNA-RNA hybrids with distinct consequences for replication and DNA dynamics at each cell cycle stage and support the conclusion that DNA-RNA hybrids are a common source of spontaneous DNA damage that remains unsolved under a deficient DDR.
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