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PMID:21191184

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Citation

Houlard, M, Artus, J, Léguillier, T, Vandormael-Pournin, S and Cohen-Tannoudji, M (2011) DNA-RNA hybrids contribute to the replication dependent genomic instability induced by Omcg1 deficiency. Cell Cycle 10:108-17

Abstract

During S phase, the replisome has to overcome many physical obstacles that can cause replication fork stalling and compromise genome integrity. Transcription is an important source of replicative stress and consequently, maintenance of genome integrity requires the protection of chromosomes from the deleterious effects arising from the interaction between nascent RNAs and template DNA, leading to stable DNA-RNA hybrids (R-loop) formation. We previously reported the essential role of Omcg1 (Ovum Mutant Candidate Gene) for cell cycle progression during early embryonic development. Here, we show that OMCG1 is a target of the cell cycle checkpoint kinases ATR/ATM and is essential for S phase progression in mouse embryonic fibroblasts. Using a conditional gene inactivation strategy, we demonstrate that OMCG1 depletion impairs cell viability as a consequence of DSB formation, checkpoint activation and replication fork collapse. We also show that no chromosome breaks were generated in non-cycling Omcg1-deficient cells. Furthermore, increased RNaseH expression significantly alleviated genomic instability in deficient fibroblasts suggesting that cotranscriptional R-loops formation contributes to the genesis of replication-dependent DSBs in these cells. Together with recent reports describing its participation to complexes involved in cotanscriptional processes, our results suggest that OMCG1 plays a role in the tight coupling between mRNA processing pathways and maintenance of genome integrity during cell cycle progression.

Links

PubMed

Keywords

Animals; Cell Cycle Proteins/genetics; Cell Cycle Proteins/physiology; Cell Survival/genetics; Cells, Cultured; Chimera/genetics; DNA Replication/genetics; Female; Genomic Instability/genetics; Mice; NIH 3T3 Cells; Nuclear Proteins/deficiency; Nuclear Proteins/genetics; Nuclear Proteins/physiology; Pregnancy; RNA, Messenger/genetics; RNA, Messenger/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SRSF1

located_in

GO:0016607: nuclear speck

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000047)

Seeded From UniProt

complete

MOUSE:ZN830

involved_in

GO:0033314: mitotic DNA replication checkpoint signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ZN830

involved_in

GO:0048478: replication fork protection

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ZN830

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ZN830

acts_upstream_of_or_within

GO:0033260: nuclear DNA replication

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4950703

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:ZN830

located_in

GO:0016607: nuclear speck

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete


See also

References

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