The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair

Naike Salvador Moreno, Jing Liu, Karen M. Haas, Laurie L. Parker, Chaitali Chakraborty, Stephen J. Kron, Kurt Hodges, Lance D. Miller, Carl Langefeld, Paul J. Robinson, Sophie A. Leliévre, Pierre Alexandre Vidi

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout 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 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 mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.

Original languageEnglish (US)
Pages (from-to)2703-2715
Number of pages13
JournalNucleic acids research
Volume47
Issue number6
DOIs
StatePublished - Apr 8 2019

Bibliographical note

Publisher Copyright:
© The Author(s) 2019.

Keywords

  • Antigens, Nuclear/physiology
  • Cells, Cultured
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair/genetics
  • DNA Repair/genetics
  • Down-Regulation
  • Female
  • HEK293 Cells
  • Humans
  • Nuclear Matrix-Associated Proteins/physiology
  • Protein Binding
  • Tumor Suppressor p53-Binding Protein 1/metabolism

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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