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

Han Sae Lee, Hye Ran Seo, Shin Ai Lee, Soohee Choi, Dongmin Kang, Jongbum Kwon

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish
Pages (from-to)3053-3066
Number of pages14
JournalBiochemical Journal
Issue number20
StatePublished - 28 Oct 2019

Bibliographical note

Funding Information:
This work was supported by grants NRF-2018R1A2B2007128 (to J.K.), NRF-2016R1C1B1013769 (to H.-S.L.), NRF-2019R1A5A6099645, and NRF-2019R1A6C1010020 from the National Research Foundation of Korea.

Publisher Copyright:
© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society


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