
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.11.612483
preprint
1
Article
53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR)
Shah Sameer Bikram http://orcid.org/0000-0001-9442-0054

Li Youhang http://orcid.org/0009-0003-8128-0154

Li Shibo http://orcid.org/0009-0002-1453-5746

Hu Qing
Wu Tong
Shi Yanmeng http://orcid.org/0009-0005-5933-7753

Nguyen Tran
Ive Isaac
Shi Linda http://orcid.org/0009-0004-8602-2813

Wang Hailong
Wu Xiaohua http://orcid.org/0000-0003-4947-3047

13 9 2024
2024.09.11.612483https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.09.11.612483
nihpp-2024.09.11.612483.pdf
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.
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pmc
