This synthetic lethality underlies the efficacy of PARP1 inhibitors in breast, ovarian, and prostate cancers that harbor inherited or acquired mutations in BRCA1 ( 31, 32).
This addiction is a singular weakness of these cancer cells, and can be targeted with therapeutic agents ( 8, 25, 29, 30), generating synthetic lethality. HR-deficient cancers become addicted to other repair pathways to resolve replication fork stress such as aNHEJ ( 26– 30). Germline or acquired mutations in BRCA1 or its interacting partner BAP1 result in defects in the HR pathway, and subsequent replication fork instability and oncogenesis ( 22– 25). After 5′ strand resection ( 13– 16), BRCA2 then loads the RAD51 recombinase onto the 3′ single-stranded DNA for invasion of the sister chromatid ( 17– 19), which results in Holliday junction formation that is later resolved by MUS81 and SLX4 ( 20, 21).
ROBERT WILLIAMSON SCITE FREE
The rate-limiting step in HR is the nucleolytic resection of the 5′ strand at a DNA free end, initiated when BRCA1/CtIP replaces 53BP1/RIF1/Shieldin at the site of DNA damage ( 9– 12). HR is the most common pathway for stressed replication fork repair and restart ( 5, 7, 8). As such, replication stress is a common etiology of genomic instability, resulting in either cell death or neoplastic transformation ( 4, 6– 8). DNA damage or nucleotide depletion can induce stalling of the replication machinery ( 3, 4), which can result in replication stress and subsequent fork collapse, with disassociation of the replication apparatus ( 5, 6). Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.ĭNA replication is not a smooth and continuous process, but rather prone to interruptions ( 1, 2). Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. Defects in DNA repair give rise to genomic instability, leading to neoplasia.
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