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

Arindam Datta, Kajal Biswas, Joshua A. Sommers, Haley Thompson, Sanket Awate, Claudia M. Nicolae, Tanay Thakar, George-Lucian Moldovan, Robert H. Shoemaker, Shyam K. Sharan and Robert M. Brosh ()
Additional contact information
Arindam Datta: NIH
Kajal Biswas: NIH
Joshua A. Sommers: NIH
Haley Thompson: NIH
Sanket Awate: NIH
Claudia M. Nicolae: The Pennsylvania State University College of Medicine
Tanay Thakar: The Pennsylvania State University College of Medicine
George-Lucian Moldovan: The Pennsylvania State University College of Medicine
Robert H. Shoemaker: NIH
Shyam K. Sharan: NIH
Robert M. Brosh: NIH

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26811-w

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