MassIVE MSV000095749

Partial Public PXD059007

PHOSPHORYLATION-DEPENDENT ASSOCIATION OF WRN WITH RPA IS REQUIRED FOR RECOVERY OF REPLICATION FORKS STALLED AT SECONDARY DNA STRUCTURES

Description

The WRN protein mutated in the premature aging disorder Werner syndrome is vital for metabolism of perturbed replication forks. Replication Protein A (RPA) robustly enhances WRN helicase activity in specific cases when tested in vitro. However, the significance of RPA-binding to WRN in vivo has remained largely unexplored. We identified several conserved phosphorylation sites in the acidic domain of WRN targeted by Casein Kinase 2 (CK2). These sites are crucial for WRN-RPA interaction in vitro and in human cells. Using the CK2-unphosphorylatable WRN mutant lacking the ability to bind RPA, we determined that the WRN-RPA complex plays a critical role in fork recovery after replication stress whereas is not necessary for the processing of replication forks or preventing DNA damage when forks stall or collapse. RPA-binding by WRN and its helicase activity are crucial for countering the persistence of G4 structures after fork stalling. Absence of WRN-RPA binding hampers fork recovery, causing single-strand DNA gaps, enlarged by MRE11, and triggering MUS81-dependent double-strand breaks which requires efficient repair by RAD51 to prevent excessive DNA damage. [doi:10.25345/C55Q4RZ1Z] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: WERNER PHOSPHOSITES

Contact

Principal Investigators:
(in alphabetical order)
FEDERICA FRATINI, ISS, Italia
Submitting User: federica_fratini
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