title: WRNIP1 protects stalled forks from degradation and promotes fork restart after replication stress.
abstract: 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.
authors.affiliation: Section of Molecular Epidemiology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leuzzi
authors.affiliation: Section of Molecular Epidemiology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Marabitti
authors.affiliation: Section of Experimental and Computational Carcinogenesis, Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Pichierri
authors.affiliation: Section of Molecular Epidemiology, Istituto Superiore di Sanità, Rome, Italy annapaola.franchitto@iss.it.
authors.forename: Annapaola
authors.identifier: 0000-0003-4232-4727
authors.initials: A
authors.lastname: Franchitto
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051135:Rad51 Recombinase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C430237:WRNIP1 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: WRNIP1; genome instability; replication fork arrest; replication fork degradation