Launching a ubiquitination cascade at DNA breaks

Abstract

The BRCA1 gene was cloned in 1994 as the first tumor suppressor of hereditary breast cancer, and it has been heavily studied ever since. The Brca1 protein is multifunctional and critical for the maintenance of genomic stability. Among its many roles, Brca1 is part of an E3 ubiquitin ligase important for homologous recombination (HR) and signaling of double-strand DNA breaks (DSBs). In response to DSBs, the checkpoint kinases ATM and ATR phosphorylate the histone variant H2AX adjacent to the breaks, which then recruits the mediator protein Mdc1 and other DNA repair and damage signaling proteins, including Brca1. Once recruited to DSBs, Brca1 colocalizes with these repair and signaling proteins in discrete nuclear foci. Both H2AX and Mdc1 are required for the formation of Brca1 foci, but how they contribute to Brca1 recruitment has not been clear. Part of this “missing link” was recently revealed. Rap80, a Brca1-associating protein, targets Brca1 to DSBs through its UIM domains, which recognize polyubiquitin chains (1–3). In this issue of PNAS, Wang and Elledge (4) present the discovery of Rnf8 as an E3 ubiquitin ligase that recognizes phosphorylated proteins at DSBs and generates the polyubiquitin chains recognized by Rap80, thereby connecting the phosphorylation- and ubiquitination-regulated steps during the recruitment of Brca1.