FOXK1 Participates in DNA Damage Response by Controlling 53BP1 Function

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2020 Aug 14

PMID 32783940

Citations 12

Authors

Mengfan Tang

Xu Feng

Guangsheng Pei

Mrinal Srivastava

Chao Wang

Zhen Chen

Siting Li

Huimin Zhang

Zhongming Zhao

Xu Li

Junjie Chen

Affiliations

Soon will be listed here.

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.

Citing Articles

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Li X, Lu J, Liu L, Li F, Xu T, Chen L Sci Rep. 2023; 13(1):7737.

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