Histone Chaperone ASF1 Acts With RIF1 To Promote DNA End Joining in BRCA1-Deficient Cells

Authors

Mengfan Tang
Zhen Chen
Chao Wang
Xu Feng
Namsoo Lee
Min Huang
Huimin Zhang
Siting Li
Yun Xiong
Junjie Chen

Publication Date

6-1-2022

Journal

Journal of Biological Chemistry

Abstract

Replication timing regulatory factor 1 (RIF1) acts downstream of p53-binding protein 53BP1 to inhibit the resection of DNA broken ends, which plays critical roles in determining the DNA double-strand break repair pathway choice between nonhomologous end joining and homologous recombination (HR). However, the mechanism by which this choice is made is not yet clear. In this study, we identified that histone chaperone protein ASF1 associates with RIF1 and regulates RIF1-dependent functions in the DNA damage response. Similar to loss of RIF1, we found that loss of ASF1 resulted in resistance to poly (ADP-ribose) polymerase (PARP) inhibition in BRCA1-deficient cells with restored HR and decreased telomere fusion in telomeric repeat-binding protein 2 (TRF2)-depleted cells. Moreover, we showed that these functions of ASF1 are dependent on its interaction with RIF1 but not on its histone chaperone activity. Thus, our study supports a new role for ASF1 in dictating double-strand break repair choice. Considering that the status of 53BP1-RIF1 axis is important in determining the outcome of PARP inhibitor-based therapy in BRCA1- or HR-deficient cancers, the identification of ASF1 function in this critical pathway uncovers an interesting connection between these S-phase events, which may reveal new strategies to overcome PARP inhibitor resistance.

Keywords

BRCA1 Protein, Cell Cycle Proteins, Cell Line, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Repair, Histone Chaperones, Humans, Molecular Chaperones, Poly(ADP-ribose) Polymerase Inhibitors, Telomere-Binding Proteins, Tumor Suppressor p53-Binding Protein 1/, ASF1, RIF1, BRCA1, 53BP1, PARPi, homologous recombination

DOI

10.1016/j.jbc.2022.101979

PMID

35472331

PMCID

PMC9127577

PubMedCentral® Posted Date

4-25-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes