Repository Community: null
http://hdl.handle.net/20.500.11750/13663
2024-03-28T23:09:23Z
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Multifaceted roles of CCAR family proteins in the DNA damage response and cancer
http://hdl.handle.net/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
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OTUD5 limits replication fork instability by organizing chromatin remodelers
http://hdl.handle.net/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
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Splicing factor SRSF3 represses translation of p21(cip1/waf1) mRNA
http://hdl.handle.net/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
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SIAH2 regulates DNA end resection and replication fork recovery by promoting CtIP ubiquitination
http://hdl.handle.net/20.500.11750/16917
Title: SIAH2 regulates DNA end resection and replication fork recovery by promoting CtIP ubiquitination
Author(s): Jeong, Seo-Yeon; Hariharasudhan, Gurusamy; Kim, Min-Ji; Lim, Ji-Yeon; Jung, Sung Mi; Choi, Eun-Ji; Chang, In-Youb; Kee, Younghoon; You, Ho Jin; Lee, Jung-Hee
Abstract: Human CtIP maintains genomic integrity primarily by promoting 5 ' DNA end resection, an initial step of the homologous recombination (HR). A few mechanisms have been suggested as to how CtIP recruitment to damage sites is controlled, but it is likely that we do not yet have full understanding of the process. Here, we provide evidence that CtIP recruitment and functioning are controlled by the SIAH2 E3 ubiquitin ligase. We found that SIAH2 interacts and ubiquitinates CtIP at its N-terminal lysine residues. Mutating the key CtIP lysine residues impaired CtIP recruitment to DSBs and stalled replication forks, DSB end resection, overall HR repair capacity of cells, and recovery of stalled replication forks, suggesting that the SIAH2-induced ubiquitination is important for relocating CtIP to sites of damage. Depleting SIAH2 consistently phenocopied these results. Overall, our work suggests that SIAH2 is a new regulator of CtIP and HR repair, and emphasizes that SIAH2-mediated recruitment of the CtIP is an important step for CtIP's function during HR repair.
2022-09-30T15:00:00Z