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Proc. Natl. Acad. Sci. USA, Jun 03 2025, 122 (22) | https://doi.org/10.1073/pnas.2415069122
Nucleoporins cooperate with Polycomb silencers to promote transcriptional repression and repair at DNA double-strand breaks
Hongseon Songa,1, Yubin Baea,1, Sangin Kimb,1, Dante Deascanisc,1, Yujin Leea, Gergely Ronad,e,f, Ethan Laned, Seo- yeoung Leea, Su-Jung Kima, Michele Paganod,e, Kyungjae Myungb,g, and Younghoon Keea,c,2
aDepartment of New Biology, Daegu Gyeongbuk Institute of Scienceand Technology, Daegu 42988, Republic of Korea;
bCenter for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea;
cDepartment of Molecular Biosciences, College of Arts and Sciences, University of South Florida, Tampa, FL 33647;
dDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
eHHMI, New York University School of Medicine, New York, NY 10016;
fInstitute of Molecular Life Sciences, Hungarian Research Network Research Centre for Natural Sciences, Budapest 1117, Hungary; and
gDepartment of Biomedical Engineering, College of Information-Bio Convergence Engineering, Ulsan National Institute of Scienceand Technology, Ulsan 44919, Republic of Korea
1H.S., Y.B., S.K., and D.D. contributed equally to this work.
2To whom correspondence may be addressed.: Younghoon Kee
aDepartment of New Biology, Daegu Gyeongbuk Institute of Scienceand Technology, Daegu 42988, Republic of Korea;
bCenter for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea;
cDepartment of Molecular Biosciences, College of Arts and Sciences, University of South Florida, Tampa, FL 33647;
dDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
eHHMI, New York University School of Medicine, New York, NY 10016;
fInstitute of Molecular Life Sciences, Hungarian Research Network Research Centre for Natural Sciences, Budapest 1117, Hungary; and
gDepartment of Biomedical Engineering, College of Information-Bio Convergence Engineering, Ulsan National Institute of Scienceand Technology, Ulsan 44919, Republic of Korea
1H.S., Y.B., S.K., and D.D. contributed equally to this work.
2To whom correspondence may be addressed.: Younghoon Kee
Abstract
DNA double-strand breaks (DSBs) are harmful lesions and major sources of genomic instability. Studies have suggested that DSBs induce local transcriptional silencing that consequently promotes genomic stability. Several factors have been proposed to actively participate in this process, including Ataxia-telangiectasia mutated (ATM) and Polycomb repressive complex 1 (PRC1). Here, we found that disrupting PRC1 clustering disrupts DSB-induced gene silencing. Interactome analysis of PHC2, a PRC1 subunit that promotes the PRC1 clustering, found several nucleoporins found in the nuclear pore complex (NPC). Similar to PHC2, depleting the nucleoporins also disrupted the DSB-induced gene silencing. We found that some of these nucleoporins, such as NUP107 and NUP43, which are members of the Y-complex of NPC, localize to DSB sites. The presence of nucleoporins and PHC2 at DSB regions was interdependent, suggesting that they act cooperatively in the DSB-induced gene silencing. We further found two structural components within NUP107 to be necessary for the transcriptional repression at DSBs: ATM/ Ataxia telangiectasia and Rad3-related-mediated phosphorylation at the Serine37 residue within the N-terminal disordered tail and the NUP133-binding surface at the C-terminus. These results provide a functional interplay among nucleoporins, ATM, and the Polycomb proteins in the DSB metabolism and underscore their emerging roles in genome stability maintenance.
논문정보
- Research article
- 2025년 06월 (BRIC 등록일 2025-06-09)
- 국내(교신)+국외 연구진
- 생명과학 > 유전학
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