WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer

Abstract

Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double-strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined.Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN-BRCA2 genetic interaction under conditions of replication stress.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry

“…The Werner syndrome ATP-dependent helicase (WRN) is a RecQ enzyme involved in the maintenance of genome integrity. WRN is associated with Werner syndrome and a predisposition to multiple cancers, such as multiple myeloma [ 28 ], myelodysplastic syndrome/acute myeloid leukemia [ 29 ], colorectal cancer [ 30 ], breast cancer [ 31 ], and ovarian cancer [ 32 ]. WRN contributes to chromosomal stability for survival in both normal and cancer cells [ 33 ].…”

Replication stress as a driver of cellular senescence and aging

“…In cooperation with RAD51, WRN also plays a structural role in counteracting unscheduled degradation of stalled forks by MRE11 nuclease 75 . Moreover, WRN helicase has been reported to promote stabilization and recovery of deprotected stalled forks in BRCA2 -deficient cells 35 , 76 . Given the essential role of WRN in fork recovery, it follows that WS cells exhibit spontaneous fork stalling, increased chromosomal instability, and early senescence features.…”