The DNA damage response acts as a safeguard against harmful DNA-RNA hybrids of different origins.
Cell Cycle
/ genetics
DNA Damage
/ genetics
DNA Replication
/ genetics
DNA, Single-Stranded
/ genetics
DNA-Binding Proteins
/ genetics
Discoidin Domain Receptors
/ genetics
Flow Cytometry
HeLa Cells
Humans
Models, Biological
Phosphoric Diester Hydrolases
/ genetics
Real-Time Polymerase Chain Reaction
Signal Transduction
/ genetics
Ubiquitin-Conjugating Enzymes
/ genetics
ATM
ATR
DNA damage response
R loop
post-replicative repair
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
16
10
2018
revised:
28
06
2019
accepted:
01
07
2019
pubmed:
25
7
2019
medline:
2
6
2020
entrez:
25
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31338941
doi: 10.15252/embr.201847250
pmc: PMC6726908
doi:
Substances chimiques
DNA, Single-Stranded
0
DNA-Binding Proteins
0
UBE2A protein, human
EC 2.3.2.23
UBE2B protein, human
EC 2.3.2.23
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Discoidin Domain Receptors
EC 2.7.10.1
Phosphoric Diester Hydrolases
EC 3.1.4.-
TDP2 protein, human
EC 3.1.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e47250Subventions
Organisme : EC|H2020|H2020 Priority Excellent Science|H2020 European Research Council ERC
ID : ERC2014 AdG669898 TARLOOP
Pays : International
Organisme : Worldwide Cancer Research
ID : WCR15-00098
Pays : United Kingdom
Organisme : Fundación Científica Asociación Española Contra el Cáncer (AECC)
Pays : International
Informations de copyright
© 2019 The Authors.
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