More modifiers move on DNA damage

Abstract

In mammalian cells the accumulation of repair proteins to double-strand breaks is a phosphorylation- and ubiquitylation-regulated process. Some of the genes that encode the kinases and ubiquitin ligases in this pathway are cancer predisposition genes, most prominently the breast cancer predisposition gene BRCA1, which encodes a ubiquitin ligase. How BRCA1 ligase activity was regulated following DNA damage was poorly understood. In this review I summarize new data that show a third post-translational modification, by the small ubiquitin like modifier SUMO, is part of the same cascade, enabling and activating DNA damage-regulated processes, including the BRCA1 ligase activity.

Figure 1. SUMO conjugation components regulate ubiquitin processes at chromatin around double-stranded DNA breaks

The PIAS4 SUMO ligase is required for the accumulation of RNF168 and subsequent activity of RNF8:RNF168 ubiquitin ligases possibly through direct SUMOylation. 53BP1 SUMO conjugation depends on PIAS4. The PIAS1 SUMO ligase is required for complete accumulation of BRCA1, possibly through RAP80, and PIAS1 and PIAS4 are both required for SUMOylation of BRCA1 which in turn increases its ubiquitin ligase activity. Ubiquitin ligases are shown as green diamonds, and ubiquitin as green circles labelled “U”. SUMO ligases are shown as light blue ovals and SUMO as small light blue ellipses labelled “S”. Chromatin components are in orange.