53BP1 regulates heterochromatin through liquid phase separation

Lei Zhang (), Xinran Geng, Fangfang Wang, Jinshan Tang, Yu Ichida, Arishya Sharma, Sora Jin, Mingyue Chen, Mingliang Tang, Franklin Mayca Pozo, Wenxiu Wang, Janet Wang, Michal Wozniak, Xiaoxia Guo, Masaru Miyagi, Fulai Jin, Yongjie Xu, Xinsheng Yao and Youwei Zhang ()
Additional contact information
Lei Zhang: Case Western Reserve University, School of Medicine
Xinran Geng: Case Western Reserve University, School of Medicine
Fangfang Wang: Jinan University
Jinshan Tang: Jinan University
Yu Ichida: Case Western Reserve University, School of Medicine
Arishya Sharma: Case Western Reserve University, School of Medicine
Sora Jin: Case Western Reserve University, School of Medicine
Mingyue Chen: Hubei University of Technology
Mingliang Tang: Wuhan University
Franklin Mayca Pozo: Case Western Reserve University, School of Medicine
Wenxiu Wang: Hubei University of Technology
Janet Wang: Case Western Reserve University, School of Medicine
Michal Wozniak: Wright State University
Xiaoxia Guo: Hubei University of Technology
Masaru Miyagi: Case Western Reserve University, School of Medicine
Fulai Jin: Case Western Reserve University, School of Medicine
Yongjie Xu: Wright State University
Xinsheng Yao: Jinan University
Youwei Zhang: Case Western Reserve University, School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Human 53BP1 is primarily known as a key player in regulating DNA double strand break (DSB) repair choice; however, its involvement in other biological process is less well understood. Here, we report a previously uncharacterized function of 53BP1 at heterochromatin, where it undergoes liquid-liquid phase separation (LLPS) with the heterochromatin protein HP1α in a mutually dependent manner. Deletion of 53BP1 results in a reduction in heterochromatin centers and the de-repression of heterochromatic tandem repetitive DNA. We identify domains and residues of 53BP1 required for its LLPS, which overlap with, but are distinct from, those involved in DSB repair. Further, 53BP1 mutants deficient in DSB repair, but proficient in LLPS, rescue heterochromatin de-repression and protect cells from stress-induced DNA damage and senescence. Our study suggests that in addition to DSB repair modulation, 53BP1 contributes to the maintenance of heterochromatin integrity and genome stability through LLPS.

Date: 2022
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DOI: 10.1038/s41467-022-28019-y

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