Interplay between Np95 and Eme1 in the DNA damage response

Abstract

Methyl methansulfonate UV sensitive clone 81 (Mus81) and essential meiotic endonuclease 1 (Eme1) form a heterodimeric endonuclease that preserves genomic integrity through the repair of DNA replication‐associated damage. Despite its role as genome guardian and tumour suppressor, our understanding of how this endonuclease is coordinated during the DNA damage response is poor. In order to identify other proteins that interact with Mus81‐Eme1, our laboratory conducted a protein interaction screen to identify and characterize proteins that interact with Eme1. One candidate identified in this screen was found to encode the carboxy‐terminal domain of Np95, a chromatin‐associated ubiquitin ligase. Np95 and Eme1 co‐localize on nuclear chromatin following exposure of cells to camptothecin, an agent that promotes the collapse of replication forks. The observed co‐localization following DNA damage was found to be dependent on an intact RING finger, the structural motif that encodes the E3 ubiquitin ligase activity of Np95. These findings for the first time, link the tumour‐suppressor Mus81‐Eme1 with the replication‐associated chromatin modifier functions of Np95 in the DNA damage response. Supported by grants from the Canadian Cancer Society through the National Cancer Institute of Canada and the Cancer Research Society.

Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

“…While our study revealed the molecular details of PI5P-mediated allosteric control of hUHRF1, defining the physiological role of such regulation events remains a major challenge. hUHRF1 interacts with several factors associated with the DNA damage response such as Eme1, TIP60, Ku70, and PARP1 (62)(63)(64). Because H3K9me3 has an important role in repair mechanisms of DNA damage (65), we speculate that hUHRF1 might recruit repair factors to H3K9me3enriched heterochromatic loci, which are otherwise inaccessible (34).…”