Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage

Abstract

NIPBL is required to load the cohesin complex on to DNA. While the canonical role of cohesin is to couple replicated sister chromatids together until the onset of mitosis, it also promotes tolerance to DNA damage. Here we show that NIPBL is recruited to DNA damage throughout the cell cycle via independent mechanisms, influenced by type of damage. Firstly, the heterochromatin protein HP1γ recruits NIPBL to DSBs through the corresponding HP1-binding motif within the N-terminus. In contrast, the C-terminal HEAT repeat domain is unable to recruit NIPBL to DSBs but independently targets NIPBL to laser microirradiation induced DNA damage. Each mechanism is dependent on the RNF8/RNF168 ubiquitylation pathway, while the recruitment of the HEAT repeat domain requires further ATM/ATR activity. Thus, NIPBL has evolved a sophisticated response to damaged DNA that is influenced by the form of damage, suggesting a highly dynamic role for NIPBL in maintaining genomic stability.