FOXK1 Participates in DNA Damage Response by Controlling 53BP1 Function

Mengfan Tang, Xu Feng, Guangsheng Pei, Mrinal Srivastava, Chao Wang, Zhen Chen, Siting Li, Huimin Zhang, Zhongming Zhao, Xu Li, Junjie Chen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

53BP1 plays a central role in dictating DNA repair choice between non-homologous end joining (NHEJ) and homologous recombination (HR), which is important for the sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis) of BRCA1-deficient cancers. In this study, we show that FOXK1 associates with 53BP1 and regulates 53BP1-dependent functions. FOXK1-53BP1 interaction is significantly enhanced upon DNA damage during the S phase in an ATM/CHK2-dependent manner, which reduces the association of 53BP1 with its downstream factors RIF1 and PTIP. Depletion of FOXK1 impairs DNA repair and induces compromised cell survival upon DNA damage. Overexpression of FOXK1 diminishes 53BP1 foci formation, which leads to resistance to PARPis and elevation of HR in BRCA1-deficient cells and decreased telomere fusion in TRF2-depleted cells. Collectively, our findings demonstrate that FOXK1 negatively regulates 53BP1 function by inhibiting 53BP1 localization to sites of DNA damage, which alters the DSB-induced protein complexes centering on 53BP1 and thus influences DNA repair choice.

Original languageEnglish (US)
Article number108018
JournalCell Reports
Volume32
Issue number6
DOIs
StatePublished - Aug 11 2020

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility
  • Functional Genomics Core

Fingerprint

Dive into the research topics of 'FOXK1 Participates in DNA Damage Response by Controlling 53BP1 Function'. Together they form a unique fingerprint.

Cite this