TFIP11 promotes replication fork reversal to preserve genome stability
Abstract Replication fork reversal, a critical protective mechanism against replication stress in higher eukaryotic cells, is orchestrated via a series of coordinated enzymatic reactions. The Bloom syndrome gene product, BLM, a member of the highly conserved RecQ helicase family, is implicated in th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45684-3 |
| _version_ | 1797273858352349184 |
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| author | Junliang Chen Mingjie Wu Yulan Yang Chunyan Ruan Yi Luo Lizhi Song Ting Wu Jun Huang Bing Yang Ting Liu |
| author_facet | Junliang Chen Mingjie Wu Yulan Yang Chunyan Ruan Yi Luo Lizhi Song Ting Wu Jun Huang Bing Yang Ting Liu |
| author_sort | Junliang Chen |
| collection | DOAJ |
| description | Abstract Replication fork reversal, a critical protective mechanism against replication stress in higher eukaryotic cells, is orchestrated via a series of coordinated enzymatic reactions. The Bloom syndrome gene product, BLM, a member of the highly conserved RecQ helicase family, is implicated in this process, yet its precise regulation and role remain poorly understood. In this study, we demonstrate that the GCFC domain-containing protein TFIP11 forms a complex with the BLM helicase. TFIP11 exhibits a preference for binding to DNA substrates that mimic the structure generated at stalled replication forks. Loss of either TFIP11 or BLM leads to the accumulation of the other protein at stalled forks. This abnormal accumulation, in turn, impairs RAD51-mediated fork reversal and slowing, sensitizes cells to replication stress-inducing agents, and enhances chromosomal instability. These findings reveal a previously unidentified regulatory mechanism that modulates the activities of BLM and RAD51 at stalled forks, thereby impacting genome integrity. |
| first_indexed | 2024-03-07T14:50:09Z |
| format | Article |
| id | doaj.art-00f7c422a4dd4430b23246b18637fc0c |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:50:09Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-00f7c422a4dd4430b23246b18637fc0c2024-03-05T19:42:43ZengNature PortfolioNature Communications2041-17232024-02-0115111710.1038/s41467-024-45684-3TFIP11 promotes replication fork reversal to preserve genome stabilityJunliang Chen0Mingjie Wu1Yulan Yang2Chunyan Ruan3Yi Luo4Lizhi Song5Ting Wu6Jun Huang7Bing Yang8Ting Liu9Zhejiang Provincial Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of MedicineThe Trauma Center, The First Affiliated Hospital, Zhejiang University School of MedicineThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityZhejiang Provincial Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of MedicineThe MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityZhejiang Provincial Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of MedicineAbstract Replication fork reversal, a critical protective mechanism against replication stress in higher eukaryotic cells, is orchestrated via a series of coordinated enzymatic reactions. The Bloom syndrome gene product, BLM, a member of the highly conserved RecQ helicase family, is implicated in this process, yet its precise regulation and role remain poorly understood. In this study, we demonstrate that the GCFC domain-containing protein TFIP11 forms a complex with the BLM helicase. TFIP11 exhibits a preference for binding to DNA substrates that mimic the structure generated at stalled replication forks. Loss of either TFIP11 or BLM leads to the accumulation of the other protein at stalled forks. This abnormal accumulation, in turn, impairs RAD51-mediated fork reversal and slowing, sensitizes cells to replication stress-inducing agents, and enhances chromosomal instability. These findings reveal a previously unidentified regulatory mechanism that modulates the activities of BLM and RAD51 at stalled forks, thereby impacting genome integrity.https://doi.org/10.1038/s41467-024-45684-3 |
| spellingShingle | Junliang Chen Mingjie Wu Yulan Yang Chunyan Ruan Yi Luo Lizhi Song Ting Wu Jun Huang Bing Yang Ting Liu TFIP11 promotes replication fork reversal to preserve genome stability Nature Communications |
| title | TFIP11 promotes replication fork reversal to preserve genome stability |
| title_full | TFIP11 promotes replication fork reversal to preserve genome stability |
| title_fullStr | TFIP11 promotes replication fork reversal to preserve genome stability |
| title_full_unstemmed | TFIP11 promotes replication fork reversal to preserve genome stability |
| title_short | TFIP11 promotes replication fork reversal to preserve genome stability |
| title_sort | tfip11 promotes replication fork reversal to preserve genome stability |
| url | https://doi.org/10.1038/s41467-024-45684-3 |
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