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CHIP and BAP1 Act in Concert to Regulate INO80 Ubiquitination and Stability for DNA Replication

Title
CHIP and BAP1 Act in Concert to Regulate INO80 Ubiquitination and Stability for DNA Replication
Authors
Seo, Hye-RanJeong, DaunLee, SunmiLee, Han-SaeLee, Shin-AiKang, Sang WonKwon, Jongbum
Ewha Authors
강상원권종범정다운
SCOPUS Author ID
강상원scopus; 권종범scopus; 정다운scopusscopus
Issue Date
2021
Journal Title
MOLECULES AND CELLS
ISSN
1016-8478JCR Link

0219-1032JCR Link
Citation
MOLECULES AND CELLS vol. 44, no. 2, pp. 101 - 115
Keywords
BRCA1-associated protein 1C-terminus of Hsp70-interacting proteinDNA replicationINO80 chromatin remodelerubiquitin
Publisher
KOREAN SOC MOLECULAR &

CELLULAR BIOLOGY
Indexed
SCIE; SCOPUS; KCI WOS
Document Type
Article
Abstract
The IN080 chromatin remodeling complex has roles in many essential cellular processes, including DNA replication. However, the mechanisms that regulate IN080 in these processes remain largely unknown. We previously reported that the stability of Ino80, the catalytic ATPase subunit of IN080, is regulated by the ubiquitin proteasome system and that BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase with tumor suppressor activity, stabilizes Ino80 via deubiquitination and promotes replication fork progression. However, the E3 ubiquitin ligase that targets Ino80 for proteasomal degradation was unknown. Here, we identified the C-terminus of Hsp70-interacting protein (CHIP), the E3 ubiquitin ligase that functions in cooperation with Hsp70, as an Ino80-interacting protein. CHIP polyubiquitinates Ino80 in a manner dependent on Hsp70. Contrary to our expectation that CHIP degrades Ino80, CHIP instead stabilizes Ino80 by extending its half-life. The data suggest that CHIP stabilizes Ino80 by inhibiting degradative ubiquitination. We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding. Interestingly, both depletion and overexpression of CHIP compromise replication fork progression with little effect on fork stalling, as similarly observed for BAP1 and Ino80, indicating that an optimal cellular level of Ino80 is important for replication fork speed but not for replication stress suppression. This work therefore idenitifes CHIP as an E3 ubiquitin ligase that stabilizes Ino80 via nondegradative ubiquitination and suggests that CHIP and BAP1 act in concert to regulate Ino80 ubiquitination to fine-tune its stability for efficient DNA replication.
DOI
10.14348/molcells.2021.2258
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자연과학대학 > 생명과학전공 > Journal papers
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