1. Exploiting replication gaps for cancer therapy.
- Author
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Cong, Ke and Cantor, Sharon B.
- Subjects
- *
CANCER treatment , *DOUBLE-strand DNA breaks , *DNA synthesis , *ANTINEOPLASTIC combined chemotherapy protocols , *BRCA genes - Abstract
Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA) mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this framework, BRCA and PARP1 share functions in DNA synthesis on the lagging strand. Thus, BRCA deficiency or "BRCAness" could reflect an inherent lagging strand problem that is vulnerable to drugs such as PARPi that also target the lagging strand, a combination that generates a toxic accumulation of replication gaps. Cong and Cantor highlight that PARP inhibition (PARPi) is synthetic lethal with BRCA -mutated cancer due to a toxic level of DNA replication gaps that they propose stem from combined lagging strand synthesis defects. They further propose that lagging strand gaps are an unappreciated consequence of other toxic combinations and anticancer drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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