BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1–Chk1 pathway, implicating checkpoint dysfunction in microcephaly

Abstract

BRIT1 [BRCT-repeat inhibitor of hTERT expression], a repressor of human telomerase function, is implicated in cellular immortalization. Here, we find that BRIT1 acts as a regulator of both the intra-S and G(2)/M checkpoints. When BRIT1 expression is depleted, cells lose the ionizing radiation (IR)-induced cell cycle arrest and become IR sensitive. BRIT1 is a chromatin-associated protein that forms irradiation-induced nuclear foci that colocalize with gamma-H2AX foci. BRIT1 is also required for the expression of both BRCA1 and the checkpoint kinase Chk1 and phosphorylation of Nbs1. Thus, the checkpoint defects in the absence of BRIT1 are likely to result from its regulation of Nbs1, BRCA1, and Chk1. BRIT1 is identical to the recently discovered MCPH1 gene, found mutant in patients with primary microcephaly. The ataxia telangiectasia mutated-Rad3 related (ATR)-Chk1 pathway is defective in Seckel syndrome, another microcephaly disorder. We propose that the microcephaly observed in patients with MCPH1 deficiencies is due to disruption of the ATR-BRCA1-Chk1 signaling pathway that is also disrupted in Seckel syndrome patients.