[Cellular functions of BRCA genes - from basic science to therapeutics]

BRCA1 and BRCA2 function for the maintenance of genome stability as "Caretakers of the genome." BRCA1 is multi- functional and interacts with ATM/ATR and their substrates to regulate various cellular functions. BRCA1 is important because of its checkpoint function at S and G₂/M phages in the DNA damage response, and controls the transcription of genes such as GADD45 or RNA poly II. BRCA1 also interacts with SWI/SNF and BACH1 to regulate chromatin re-modeling. BRCA2 is also multi-functional, and regulates the repair of DNA double-strand breaks in cooperation with the MRN complex and RPA. BRCA2 interacts with Rad51 to directly repair DNA damage. In addition, BRCA2 regulates cytokinesis and centrosome duplication. New treatment is developed with inhibitors of poly(ADP-ribose)polymerase(PARP)for BRCA-deficient cells. PARPs repair single-strand DNA breaks, and inhibition of PARPs is considered to break the replication fork and increase the effect of anti-cancer drugs. Inhibition of PARPs leads to the conversion of single-strand breaks(SSB)to double-strand breaks(DSB). Because BRCA1- or BRCA2-deficient cells are unable to efficiently complete homologous recombination, PARP inhibition in these cells causes a high degree of genomic instability and eventual cell death termed "synthetic lethality. "This synthetic lethal approach has been validated in studies that show striking single-agent activity of PARP inhibitors in preclinical models of BRCA1 and BRCA2 inactivation.