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DSB repair pathway choice is regulated by recruitment of 53BP1 through cell cycle-dependent regulation of Sp1
Journal article   Open access   Peer reviewed

DSB repair pathway choice is regulated by recruitment of 53BP1 through cell cycle-dependent regulation of Sp1

Michelle L. Swift, Kate Beishline, Samuel Flashner and Jane Azizkhan-Clifford
Cell reports (Cambridge), v 34(11), 108840
16 Mar 2021
DOI: https://doi.org/10.1016/j.celrep.2021.108840
PMID: 33730584
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1016/j.celrep.2021.108840View
Published, Version of Record (VoR)CC BY-NC-ND V4.0,  Open

Abstract

53BP1 BRCA1 cell cycle DSB repair NHEJ Sp1 synthetic lethality
Although many of the factors, epigenetic changes, and cell cycle stages that distinguish repair of double-strand breaks (DSBs) by homologous recombination (HR) from non-homologous end joining (NHEJ) are known, the underlying mechanisms that determine pathway choice are incompletely understood. Previously, we found that the transcription factor Sp1 is recruited to DSBs and is necessary for repair. Here, we demonstrate that Sp1 localizes to DSBs in G1 and is necessary for recruitment of the NHEJ repair factor, 53BP1. Phosphorylation of Sp1-S59 in early S phase evicts Sp1 and 53BP1 from the break site; inhibition of that phosphorylation results in 53BP1 and Sp1 remaining at DSBs in S phase cells, precluding BRCA1 binding and suppressing HR. Expression of Sp1-S59A increases sensitivity of BRCA1+/+ cells to poly (ADP-ribose) polymerase (PARP) inhibition similar to BRCA1 deficiency. These data demonstrate how Sp1 integrates the cell cycle and DSB repair pathway choice to favor NHEJ. [Display omitted] •Sp1 is necessary for the recruitment of 53BP1 for the repair of DSBs via NHEJ•Phosphorylation of Sp1 at the G1/S boundary evicts Sp1 and 53BP1 from DSBs•Failure to evict Sp1 in S phase perturbs BRCA1 binding, resulting in PARPi sensitivity Swift et al. show that Sp1 is necessary for the recruitment of 53BP1 and DSB repair via NHEJ. Phosphorylation of Sp1 by cyclinA/cdk2 at the G1/S boundary evicts Sp1 and 53BP1 from DSBs in S phase, permitting BRCA1 binding. Failure to evict Sp1 in S phase results in PARPi sensitivity.

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37 citations in Web of Science
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Collaboration types
Domestic collaboration
Web of Science research areas
Cell Biology
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