Abstract A46: Nup153 and Nup50 promote recruitment of 53BP1 to DNA repair foci by antagonizing BRCA1-dependent events

This study focuses on an unexpected role for particular nuclear pore proteins in the antagonism between the DNA repair factors BRCA1 and 53BP1, and the impact this has on the response to poly(A) ribose polymerase (PARP) inhibition. Repair of DNA double strand breaks, a cornerstone of genomic integrity, typically follows one of two distinct pathways: the high fidelity process of homologous recombination (HR) repair, in which BRCA1 plays a key role, and the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in binding to damage sites, where it protects the DNA ends from resection and prevents HR from occurring. Conversely, BRCA1 binding counteracts 53BP1-mediated events to promote HR repair. While mutual antagonism between BRCA1 and 53BP1 has been appreciated for some time, factors that modulate this relationship are only beginning to be elucidated. The nuclear pore component Nup153 has previously been implicated in the DNA damage response, specifically in promoting nuclear import of 53BP1. To further explore the role of Nup153 in this context, we engineered an additional strong nuclear localization sequence (NLS) on 53BP1 and found that this overrides the requirement for Nup153 in nuclear import of 53BP1. While 53BP1-NLS is recruited normally to DNA damage foci in control-treated cells, its accumulation at these sites is still severely impaired in Nup153-depleted ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research