Accurate handling of stalled replication forks is crucial for the maintenance of genome stability. RAD51 defends stalled replication forks from nucleolytic attack, which otherwise can threaten genome stability. However, the identity of other factors that can collaborate with RAD51 in this task is poorly elucidated. Here, we establish that human Werner helicase interacting protein 1 (WRNIP1) is localized to stalled replication forks and cooperates with RAD51 to safeguard fork integrity. We show that WRNIP1 is directly involved in preventing uncontrolled MRE11‐mediated degradation of stalled replication forks by promoting RAD51 stabilization on ssDNA. We further demonstrate that replication fork protection does not require the ATPase activity of WRNIP1 that is however essential to achieve the recovery of perturbed replication forks. Loss of WRNIP1 or its catalytic activity causes extensive DNA damage and chromosomal aberrations. Intriguingly, downregulation of the anti‐recombinase FBH1 can compensate for loss of WRNIP1 activity, since it attenuates replication fork degradation and chromosomal aberrations in WRNIP1‐deficient cells. Therefore, these findings unveil a unique role for WRNIP1 as a replication fork‐protective factor in maintaining genome stability.
The hitherto poorly characterized ATPase WRNIP, originally identified as an interactor of the Werner syndrome helicase, is found to cooperate with the RAD51 recombinase in the protection of stalled replication forks.
WRNIP1 protects stalled replication forks from degradation.
The ATPase activity of WRNIP1 promotes fork restart after replication stress.
WRNIP1 contributes to the stabilization of RAD51 on stalled replication forks.
Downregulation of the anti‐recombinase FBH1 compensates for loss of WRNIP1 activity.
The EMBO Journal (2016) 35: 1437–1451
- Received October 13, 2015.
- Revision received April 28, 2016.
- Accepted April 29, 2016.
- © 2016 The Authors