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Publication Detail

Title: WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells.

Authors: Datta, Arindam; Biswas, Kajal; Sommers, Joshua A; Thompson, Haley; Awate, Sanket; Nicolae, Claudia M; Thakar, Tanay; Moldovan, George-Lucian; Shoemaker, Robert H; Sharan, Shyam K; Brosh Jr, Robert M

Published In Nat Commun, (2021 11 12)

Abstract: The tumor suppressor BRCA2 protects stalled forks from degradation to maintain genome stability. However, the molecular mechanism(s) whereby unprotected forks are stabilized remains to be fully characterized. Here, we demonstrate that WRN helicase ensures efficient restart and limits excessive degradation of stalled forks in BRCA2-deficient cancer cells. In vitro, WRN ATPase/helicase catalyzes fork restoration and curtails MRE11 nuclease activity on regressed forks. We show that WRN helicase inhibitor traps WRN on chromatin leading to rapid fork stalling and nucleolytic degradation of unprotected forks by MRE11, resulting in MUS81-dependent double-strand breaks, elevated non-homologous end-joining and chromosomal instability. WRN helicase inhibition reduces viability of BRCA2-deficient cells and potentiates cytotoxicity of a poly (ADP)ribose polymerase (PARP) inhibitor. Furthermore, BRCA2-deficient xenograft tumors in mice exhibited increased DNA damage and growth inhibition when treated with WRN helicase inhibitor. This work provides mechanistic insight into stalled fork stabilization by WRN helicase when BRCA2 is deficient.

PubMed ID: 34772932 Exiting the NIEHS site

MeSH Terms: Animals; BRCA2 Protein/genetics*; BRCA2 Protein/metabolism*; Cell Line, Tumor; DNA Damage; DNA Helicases/genetics*; DNA Helicases/metabolism*; DNA Replication/physiology; Female; Genomic Instability; Heterografts; MRE11 Homologue Protein/metabolism; Mice; Mice, Nude; Neoplasms/genetics*; Poly (ADP-Ribose) Polymerase-1/drug effects; Poly (ADP-Ribose) Polymerase-1/metabolism; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology; Werner Syndrome Helicase/genetics*; Werner Syndrome Helicase/metabolism*

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