Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate replication restart

Somyajit, Kumar and Saxena, Sneha and Babu, Sharath and Mishra, Anup and Nagaraju, Ganesh (2015) Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate replication restart. In: NUCLEIC ACIDS RESEARCH, 43 (20). pp. 9835-9855.

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Abstract

Mammalian RAD51 paralogs are implicated in the repair of collapsed replication forks by homologous recombination. However, their physiological roles in replication fork maintenance prior to fork collapse remain obscure. Here, we report on the role of RAD51 paralogs in short-term replicative stress devoid of DSBs. We show that RAD51 paralogs localize to nascent DNA and common fragile sites upon replication fork stalling. Strikingly, RAD51 paralogs deficient cells exhibit elevated levels of 53BP1 nuclear bodies and increased DSB formation, the latter being attributed to extensive degradation of nascent DNA at stalled forks. RAD51C and XRCC3 promote the restart of stalled replication in an ATP hydrolysis dependent manner by disengaging RAD51 and other RAD51 paralogs from the halted forks. Notably, we find that Fanconi anemia (FA)-like disorder and breast and ovarian cancer patient derived mutations of RAD51C fails to protect replication fork, exhibit under-replicated genomic regions and elevated micro-nucleation. Taken together, RAD51 paralogs prevent degradation of stalled forks and promote the restart of halted replication to avoid replication fork collapse, thereby maintaining genomic integrity and suppressing tumorigenesis.

Item Type:	Journal Article
Publication:	NUCLEIC ACIDS RESEARCH
Publisher:	OXFORD UNIV PRESS
Additional Information:	Copy right for this article belongs to the OXFORD UNIV PRESS, GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	14 Jan 2016 06:10
Last Modified:	14 Jan 2016 06:10
URI:	http://eprints.iisc.ac.in/id/eprint/53093

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