Defining and Modulating ‘BRCAness’

Research output: Contribution to journalReview articlepeer-review

17 Scopus citations

Abstract

The concept of ‘BRCAness’ defines the pathogenesis and vulnerability of multiple cancers. The canonical definition of BRCAness is a defect in homologous recombination repair, mimicking BRCA1 or BRCA2 loss. In turn, BRCA-deficient cells utilize error-prone DNA-repair pathways, causing increased genomic instability, which may be responsible for their sensitivity to DNA damaging agents and poly-(ADP)-ribose polymerase inhibitors (PARPis). However, recent work has expanded the mechanistic basis of BRCAness, to include defects in replication fork protection (RFP). Here, we broaden the definition of BRCAness to include RFP and regulatory mechanisms that cause synthetic lethality with PARPis. We highlight these recent discoveries, which include mechanisms of RFP regulation, DNA damage checkpoint proteins, as well as kinases that regulate BRCA1/2 function. Importantly, many of these emerging mechanisms may be targeted for inhibition with small molecule inhibitors, thus inducing BRCAness in a much larger subset of BRCA-proficient tumors, with significant translational potential.

Original languageEnglish
Pages (from-to)740-751
Number of pages12
JournalTrends in Cell Biology
Volume29
Issue number9
DOIs
StatePublished - Sep 2019

Keywords

  • BRCA1
  • BRCA2
  • PARP
  • chemotherapy resistance
  • homologous recombination
  • replication fork protection

Fingerprint Dive into the research topics of 'Defining and Modulating ‘BRCAness’'. Together they form a unique fingerprint.

Cite this