https://scholar.dgist.ac.kr/handle/20.500.11750/13663 2026-04-09T22:13:08Z https://scholar.dgist.ac.kr/handle/20.500.11750/58448 Title: Nucleoporins cooperate with Polycomb silencers to promote transcriptional repression and repair at DNA double-strand breaks Author(s): Song, Hongseon; Bae, Yubin; Kim, Sangin; Deascanis, Dante; Lee, Yujin; Rona, Gergely; Lane, Ethan; Lee, Seo-Yeoung; Kim, Su-Jung; Pagano, Michele; Myung, Kyungjae; Kee, Younghoon 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. Copyright © 2025 the Author(s). 2025-05-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/47969 Title: Multifaceted roles of CCAR family proteins in the DNA damage response and cancer Author(s): Lugano, D.; Barrett, L.; Westerheide, S.D.; Kee, Younghoon Abstract: The cell cycle apoptosis regulator (CCAR) family of proteins consists of two proteins, CCAR1 and CCAR2, that play a variety of roles in cellular physiology and pathology. These multidomain proteins are able to perform multiple interactions and functions, playing roles in processes such as stress responses, metabolism, and the DNA damage response. The evolutionary conservation of CCAR family proteins allows their study in model organisms such as Caenorhabditis elegans, where a role for CCAR in aging was revealed. This review particularly highlights the multifaceted roles of CCAR family proteins and their implications in the DNA damage response and in cancer biology. © 2023, The Author(s). 2024-01-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/47705 Title: OTUD5 limits replication fork instability by organizing chromatin remodelers Author(s): de Vivo, Angelo; Song, Hongseon; Lee, Yujin; Tirado-Class, Neysha; Sanchez, Anthony; Westerheide, Sandy; Dungrawala, Huzefa; Kee, Younghoon Abstract: Proper regulation of replication fork progression is important for genomic maintenance. Subverting the transcription-induced conflicts is crucial in preserving the integrity of replication forks. Various chromatin remodelers, such as histone chaperone and histone deacetylases are known to modulate replication stress, but how these factors are organized or collaborate are not well understood. Here we found a new role of the OTUD5 deubiquitinase in limiting replication stress. We found that OTUD5 is recruited to replication forks, and its depletion causes replication fork stress. Through its C-terminal disordered tail, OTUD5 assembles a complex containing FACT, HDAC1 and HDAC2 at replication forks. A cell line engineered to specifically uncouple FACT interaction with OTUD5 exhibits increases in FACT loading onto chromatin, R-loop formation, and replication fork stress. OTUD5 mediates these processes by recruiting and stabilizing HDAC1 and HDAC2, which decreases H4K16 acetylation and FACT recruitment. Finally, proteomic analysis revealed that the cells with deficient OTUD5-FACT interaction activates the Fanconi Anemia pathway for survival. Altogether, this study identified a new interaction network among OTUD5-FACT-HDAC1/2 that limits transcription-induced replication stress. © 2023 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. 2023-09-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/17447 Title: Splicing factor SRSF3 represses translation of p21(cip1/waf1) mRNA Author(s): Kim, Jeeho; Park, Ra Young; Kee, Younghoon; Jeong, Sunjoo; Ohn, Takbum Abstract: Serine/arginine-rich splicing factor 3 (SRSF3) is an RNA binding protein that most often regulates gene expression at the splicing level. Although the role of SRSF3 in mRNA splicing in the nucleus is well known, its splicing-independent role outside of the nucleus is poorly understood. Here, we found that SRSF3 exerts a translational control of p21 mRNA. Depletion of SRSF3 induces cellular senescence and increases the expression of p21 independent of p53. Consistent with the expression patterns of SRSF3 and p21 mRNA in the TCGA database, SRSF3 knockdown increases the p21 mRNA level and its translation efficiency as well. SRSF3 physically associates with the 3′UTR region of p21 mRNA and the translational initiation factor, eIF4A1. Our study proposes a model in which SRSF3 regulates translation by interacting with eIF4A1 at the 3′UTR region of p21 mRNA. We also found that SRSF3 localizes to the cytoplasmic RNA granule along with eIF4A1, which may assist in translational repression therein. Thus, our results provide a new mode of regulation for p21 expression, a crucial regulator of the cell cycle and senescence, which occurs at the translational level and involves SRSF3. © 2022, The Author(s). 2022-10-31T15:00:00Z