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PIF1 helicase promotes break‐induced replication in mammalian cells
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- Shibo Li
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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- Hailong Wang
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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- Sanaa Jehi
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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- Jun Li
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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- Shuo Liu
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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- Zi Wang
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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- Lan Truong
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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- Takuya Chiba
- Biomedical Gerontology Laboratory Department of Health Science and Social Welfare School of Human Sciences Waseda University Tokorozawa Japan
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- Zefeng Wang
- CAS Key Laboratory of Computational Biology University of Chinese Academy of Sciences Shanghai Institute of Biological Sciences Chinese Academy of Sciences Shanghai China
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- Xiaohua Wu
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA USA
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Description
Break-induced replication (BIR) is a specialized homologous-recombination pathway for DNA double-strand break (DSB) repair, which often induces genome instability. In this study, we establish EGFP-based recombination reporters to systematically study BIR in mammalian cells and demonstrate an important role of human PIF1 helicase in promoting BIR. We show that at endonuclease cleavage sites, PIF1-dependent BIR is used for homology-initiated recombination requiring long track DNA synthesis, but not short track gene conversion (STGC). We also show that structure formation-prone AT-rich DNA sequences derived from common fragile sites (CFS-ATs) induce BIR upon replication stress and oncogenic stress, and PCNA-dependent loading of PIF1 onto collapsed/broken forks is critical for BIR activation. At broken replication forks, even STGC-mediated repair of double-ended DSBs depends on POLD3 and PIF1, revealing an unexpected mechanism of BIR activation upon replication stress that differs from the conventional BIR activation model requiring DSB end sensing at endonuclease-generated breaks. Furthermore, loss of PIF1 is synthetically lethal with loss of FANCM, which is involved in protecting CFS-ATs. The breast cancer-associated PIF1 mutant L319P is defective in BIR, suggesting a direct link of BIR to oncogenic processes.
Journal
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- The EMBO Journal
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The EMBO Journal 40 (8), 2021-01-20
Springer Science and Business Media LLC
