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BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress

Title
BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress
Authors
Lee H.-S.Seo H.-R.Lee S.-A.Choi S.Kang D.Kwon J.
Ewha Authors
권종범강동민이한새
SCOPUS Author ID
권종범scopus; 강동민scopus
Issue Date
2019
Journal Title
Biochemical Journal
ISSN
0264-6021JCR Link
Citation
Biochemical Journal vol. 476, no. 20, pp. 3053 - 3066
Publisher
Portland Press Ltd
Indexed
SCI; SCIE; SCOPUS scopus
Document Type
Article
Abstract
The recovery from replication stress by restarting stalled forks to continue DNA synthesis is crucial for maintaining genome stability and thereby preventing diseases such as cancer. We previously showed that BRCA1-associated protein 1 (BAP1), a nuclear deubiquitinase with tumor suppressor activity, promotes replication fork progression by stabilizing the INO80 chromatin remodeler via deubiquitination and recruiting it to replication forks during normal DNA synthesis. However, whether BAP1 functions in DNA replication under stress conditions is unknown. Here, we show that BAP1 depletion reduces S-phase progression and DNA synthesis after treatment with hydroxyurea (HU). BAP1-depleted cells exhibit a defect in the restart of HU-induced stalled replication forks, which is recovered by the ectopic expression of INO80. Both BAP1 and INO80 bind chromatin at replication forks upon HU treatment. BAP1 depletion abrogates the binding of INO80 to replication forks and increases the formation of RAD51 foci following HU treatment. BAP1-depleted cells show hypersensitivity to HU treatment, which is rescued by INO80 expression. These results suggest that BAP1 promotes the restart of stress-induced stalled replication forks by recruiting INO80 to the stalled forks. This function of BAP1 in replication stress recovery may contribute to its ability to suppress genome instability and cancer development. © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
DOI
10.1042/BCJ20190622
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자연과학대학 > 생명과학전공 > Journal papers
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