A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein

Abstract

BRCA1 is a central component of the DNA damage response mechanism and defects in BRCA1 confer sensitivity to a broad range of DNA damaging agents. BRCA1 is required for homologous recombination and DNA damage-induced S and G 2 /M phase arrest. We show here that BRCA1 is required for ATM-and ATR-dependent phosphorylation of p53, c-Jun, Nbs1 and Chk2 following exposure to ionizing or ultraviolet radiation, respectively, and is also required for ATM phosphorylation of CtIP. In contrast, DNA damageinduced phosphorylation of the histone variant H2AX is independent of BRCA1. We also show that the presence of BRCA1 is dispensable for DNA damageinduced phosphorylation of Rad9, Hus1 and Rad17, and for the relocalization of Rad9 and Hus1. We propose that BRCA1 facilitates the ability of ATM and ATR to phosphorylate downstream substrates that directly in¯uence cell cycle checkpoint arrest and apoptosis, but that BRCA1 is dispensable for the phosphorylation of DNA-associated ATM and ATR substrates.

BRCA1-BARD1 Complexes Are Required for p53Ser-15 Phosphorylation and a G1/S Arrest following Ionizing Radiation-induced DNA Damage

“…These findings indicate that the BRCA1-BARD1 complex acts downstream in the DNA damage response. A recent study has reported that a subset of ATM and ATR substrates requires BRCA1 for phosphorylation (45). , which is bound to BARD1.…”

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

“…Phosphorylation of BRCA1 on these sites is closely linked to S-phase and G2/M checkpoints (Xu et al, 2001. Several studies also showed that BRCA1 is required for optimal levels of ATM-dependent phosphorylation of p53, c-Jun, Nbs1, Chk2, CtIP and SMC1, although the BRCA1 dependence of some of these phosphorylation events is controversial (Foray et al, 2003;Fabbro et al, 2004;Kitagawa et al, 2004). Kitagawa et al (2004) also showed that BRCA1 is required for focus formation by autophosphorylated ATM.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…Although the type of DNA lesion preferentially targeted by each mechanism is known, 183 notably, there is evidence for direct interaction between components of the different repair systems as well as between DNA repair and the p53 pathway. [186][187][188][189][190][191][192][193][194] Although loss of apoptotic/senescent function in theory should be expected to cause therapy resistance, the opposite may be the case in DNA repair. Drugs like alkylating agents generate 8-oxoguanine and single-strand breaks subject to repair by BER, whereas platinum-containing compounds generate interstrand crosslinks and double-strand breaks.…”