BRCA1 16 years later: DNA damage-induced BRCA1 shuttling

Abstract

The tumor suppressor, breast cancer susceptibility gene 1 (BRCA1), plays an integral role in the maintenance of genome stability and, in particular, the cellular response to DNA damage. Here, the emerging role of BRCA1 in nonhomologous end-joining-mediated DNA repair following DNA damage will be reviewed, as well as the activation of apoptotic pathways. The control of these functions via DNA damage-induced BRCA1 shuttling will also be discussed, in particular BRCA1 shuttling induced by erlotinib and irradiation. Finally, the potential targeting of BRCA1 shuttling as a novel strategy to sensitize cells to DNA damage will be entertained.

Fig. 1.

Model depicting how BRCA1 protects the genome. BRCA1 protects the genome through facilitating the repair of damaged DNA and, if unsuccessful, is shuttled to other cellular compartments to activate cell death pathways to eliminate cells with persistent DNA lesions. In contrast, survival of cells carrying damaged DNA will lead to genomic instability and resistance to DNA damage-based cancer therapy.

Fig. 2.

Model depicting potential targeting of BRCA1 to the cytoplasm to inhibit repair of DSBs and to sensitize cells to DNA-damaging agents. Following DNA damage, BRCA1 facilitates the repair of DNA in the nucleus. By targeting BRCA1 subcellular localization (i.e. depletion of nuclear BRCA1 or translocation of BRCA1 DNA-damaging agents.