NuMA is a negative regulator of 53BP1 in DNA double-strand break repair [article]

Naike Salvador-Moreno, Jing Liu, Karen Haas, Laurie Parker, Chaitali Chakraborty, Stephen Kron, Kurt Hodges, Lance Miller, Paul Robinson, Sophie Lelievre, Pierre-Alexandre Vidi
2017 bioRxiv   pre-print
Accumulation of 53BP1 at DNA breaks determines DNA repair pathway choice and promotes checkpoint activation. Here, we show regulation of 53BP1 beyond repair foci. 53BP1 movements are constrained in the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma, NuMA
more » ... ast carcinoma, NuMA prevents 53BP1 accumulation at DNA breaks and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a new mechanism that involves the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.
doi:10.1101/230706 fatcat:cssm7zgrzbd2rbnezo6gr2x4by