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

Authors
  • Mackay, Douglas R1
  • Howa, Amanda C2
  • Werner, Theresa L3
  • Ullman, Katharine S1
  • 1 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA [email protected] [email protected]
  • 2 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
  • 3 Department of Medicine, Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Oct 01, 2017
Volume
130
Issue
19
Pages
3347–3359
Identifiers
DOI: 10.1242/jcs.203513
PMID: 28751496
Source
Medline
Keywords
License
Unknown

Abstract

DNA double-strand breaks are typically repaired through either the high-fidelity process of homologous recombination (HR), in which BRCA1 plays a key role, or 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. The nucleoporin Nup153 has been implicated in the DNA damage response, attributed to a role in promoting nuclear import of 53BP1. Here, we define a distinct requirement for Nup153 in 53BP1 intranuclear targeting to damage foci and report that Nup153 likely facilitates the role of another nucleoporin, Nup50, in 53BP1 targeting. The requirement for Nup153 and Nup50 in promoting 53BP1 recruitment to damage foci induced by either etoposide or olaparib is abrogated in cells deficient for BRCA1 or its partner BARD1, but not in cells deficient for BRCA2. Together, our results further highlight the antagonistic relationship between 53BP1 and BRCA1, and place Nup153 and Nup50 in a molecular pathway that regulates 53BP1 function by counteracting BRCA1-mediated events.

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