MassIVE MSV000095749

Partial Public PXD059007

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

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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

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