53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR)

Sameer Bikram Shah, Youhang Li, Shibo Li, Qing Hu, Tong Wu, Yanmeng Shi, Tran Nguyen, Isaac Ive, Linda Shi, Hailong Wang and Xiaohua Wu ()
Additional contact information
Sameer Bikram Shah: The Scripps Research Institute
Youhang Li: The Scripps Research Institute
Shibo Li: The Scripps Research Institute
Qing Hu: The Scripps Research Institute
Tong Wu: The Scripps Research Institute
Yanmeng Shi: The Scripps Research Institute
Tran Nguyen: The Scripps Research Institute
Isaac Ive: The Scripps Research Institute
Linda Shi: San Diego
Hailong Wang: Capital Normal University
Xiaohua Wu: The Scripps Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.

Date: 2024
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DOI: 10.1038/s41467-024-52916-z

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