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

Nucleic Acids Research
Naike Salvador MorenoPierre-Alexandre Vidi

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.

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Citations

Jul 19, 2019·Nucleic Acids Research·Jakub A KochanPrzemek M Krawczyk
Jun 18, 2020·Cancers·Marcus WurlitzerThorsten Rieckmann
Aug 28, 2020·Molecular Biology of the Cell·Ashwathi RajeevanSachin Kotak
Oct 13, 2020·The Journal of Cell Biology·Andrea Serra-MarquesSophie Dumont
Jan 16, 2022·Cell Biology International·Mengdi ZhangJing Liu

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Datasets Mentioned

BETA
MSV000083293

Methods Mentioned

BETA
chromosomal aberrations
ubiquitination
transfection
PCR
Fluorescence correlation spectroscopy
Co-IP
flow
flow cytometry
chromosomal
RNA-seq

Software Mentioned

Proteome
MathWorks
FCS
MATLAB
Mascot
ProteoWizard
PicoQuant
OncoLnc
MEM
ImageJ

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