TY - JOUR
T1 - Defining and Modulating ‘BRCAness’
AU - Byrum, Andrea K.
AU - Vindigni, Alessandro
AU - Mosammaparast, Nima
N1 - Publisher Copyright:
© 2019
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - BRCA1
KW - BRCA2
KW - PARP
KW - chemotherapy resistance
KW - homologous recombination
KW - replication fork protection
UR - http://www.scopus.com/inward/record.url?scp=85069713767&partnerID=8YFLogxK
U2 - 10.1016/j.tcb.2019.06.005
DO - 10.1016/j.tcb.2019.06.005
M3 - Review article
C2 - 31362850
AN - SCOPUS:85069713767
SN - 0962-8924
VL - 29
SP - 740
EP - 751
JO - Trends in Cell Biology
JF - Trends in Cell Biology
IS - 9
ER -