Genes & development最新文献_第9页

Molecular basis for PHF7-mediated ubiquitination of histone H3. phf7介导组蛋白H3泛素化的分子基础。

IF 7.5 1区生物学

Genes & development Pub Date : 2023-12-26 DOI: 10.1101/gad.350989.123

Hyun Sik Lee, Injin Bang, Junghyun You, Tae-Kyeong Jeong, Chang Rok Kim, Minsang Hwang, Jong-Seo Kim, Sung Hee Baek, Ji-Joon Song, Hee-Jung Choi

{"title":"Molecular basis for PHF7-mediated ubiquitination of histone H3.","authors":"Hyun Sik Lee, Injin Bang, Junghyun You, Tae-Kyeong Jeong, Chang Rok Kim, Minsang Hwang, Jong-Seo Kim, Sung Hee Baek, Ji-Joon Song, Hee-Jung Choi","doi":"10.1101/gad.350989.123","DOIUrl":"10.1101/gad.350989.123","url":null,"abstract":"The RING-type E3 ligase has been known for over two decades, yet its diverse modes of action are still the subject of active research. Plant homeodomain (PHD) finger protein 7 (PHF7) is a RING-type E3 ubiquitin ligase responsible for histone ubiquitination. PHF7 comprises three zinc finger domains: an extended PHD (ePHD), a RING domain, and a PHD. While the function of the RING domain is largely understood, the roles of the other two domains in E3 ligase activity remain elusive. Here, we present the crystal structure of PHF7 in complex with the E2 ubiquitin-conjugating enzyme (E2). Our structure shows that E2 is effectively captured between the RING domain and the C-terminal PHD, facilitating E2 recruitment through direct contact. In addition, through in vitro binding and functional assays, we demonstrate that the N-terminal ePHD recognizes the nucleosome via DNA binding, whereas the C-terminal PHD is involved in histone H3 recognition. Our results provide a molecular basis for the E3 ligase activity of PHF7 and uncover the specific yet collaborative contributions of each domain to the PHF7 ubiquitination activity.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10760634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138295058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of the SF3B1-SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing. SF3B1-SUGP1界面的表征揭示了许多癌症突变如何导致mRNA错剪接。

IF 7.5 1区生物学

Genes & development Pub Date : 2023-12-26 DOI: 10.1101/gad.351154.123

Jian Zhang, Jindou Xie, Ji Huang, Xiangyang Liu, Ruihong Xu, Jonas Tholen, Wojciech P Galej, Liang Tong, James L Manley, Zhaoqi Liu

{"title":"Characterization of the SF3B1-SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing.","authors":"Jian Zhang, Jindou Xie, Ji Huang, Xiangyang Liu, Ruihong Xu, Jonas Tholen, Wojciech P Galej, Liang Tong, James L Manley, Zhaoqi Liu","doi":"10.1101/gad.351154.123","DOIUrl":"10.1101/gad.351154.123","url":null,"abstract":"The spliceosomal gene SF3B1 is frequently mutated in cancer. While it is known that SF3B1 hotspot mutations lead to loss of splicing factor SUGP1 from spliceosomes, the cancer-relevant SF3B1-SUGP1 interaction has not been characterized. To address this issue, we show by structural modeling that two regions flanking the SUGP1 G-patch make numerous contacts with the region of SF3B1 harboring hotspot mutations. Experiments confirmed that all the cancer-associated mutations in these regions, as well as mutations affecting other residues in the SF3B1-SUGP1 interface, not only weaken or disrupt the interaction but also alter splicing similarly to SF3B1 cancer mutations. Finally, structural modeling of a trimeric protein complex reveals that the SF3B1-SUGP1 interaction \"loops out\" the G-patch for interaction with the helicase DHX15. Our study thus provides an unprecedented molecular view of a protein complex essential for accurate splicing and also reveals that numerous cancer-associated mutations disrupt the critical SF3B1-SUGP1 interaction.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10760632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136397192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A nonneural miRNA cluster mediates hearing via repression of two neural targets 一个非神经miRNA集群通过抑制两个神经目标介导听力

IF 10.5 1区生物学

Genes & development Pub Date : 2023-12-18 DOI: 10.1101/gad.351052.123

Binglong Zhang, Hong Duan, Joshua Kavaler, Lu Wei, Daniel F. Eberl, Eric C. Lai

引用次数: 0

Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription 限制因子与 Symplekin 和 PNUTS 协同终止基因外转录

IF 10.5 1区生物学

Genes & development Pub Date : 2023-12-13 DOI: 10.1101/gad.351057.123

Marta Russo, Viviana Piccolo, Danilo Polizzese, Elena Prosperini, Carolina Borriero, Sara Polletti, Fabio Bedin, Mattia Marenda, Davide Michieletto, Gaurav Madappa Mandana, Simona Rodighiero, Alessandro Cuomo, Gioacchino Natoli

{"title":"Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription","authors":"Marta Russo, Viviana Piccolo, Danilo Polizzese, Elena Prosperini, Carolina Borriero, Sara Polletti, Fabio Bedin, Mattia Marenda, Davide Michieletto, Gaurav Madappa Mandana, Simona Rodighiero, Alessandro Cuomo, Gioacchino Natoli","doi":"10.1101/gad.351057.123","DOIUrl":"https://doi.org/10.1101/gad.351057.123","url":null,"abstract":"Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic cis-regulatory elements. The Restrictor complex, composed of the Pol II-interacting protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription at thousands of extragenic sites in mammalian genomes. Restrictor-driven termination does not involve nascent RNA cleavage, and its interplay with other termination machineries is unclear. Here we show that efficient termination at Restrictor-controlled extragenic transcription units involves the recruitment of the protein phosphatase 1 (PP1) regulatory subunit PNUTS, a negative regulator of the SPT5 elongation factor, and Symplekin, a protein associated with RNA cleavage complexes but also involved in cleavage-independent and phosphatase-dependent termination of noncoding RNAs in yeast. PNUTS and Symplekin act synergistically with, but independently from, Restrictor to dampen processive extragenic transcription. Moreover, the presence of limiting nuclear levels of Symplekin imposes a competition for its recruitment among multiple transcription termination machineries, resulting in mutual regulatory interactions. Hence, by synergizing with Restrictor, Symplekin and PNUTS enable efficient termination of processive, long-range extragenic transcription.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138582565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The steroid hormone ADIOL promotes learning by reducing neural kynurenic acid levels 类固醇激素 ADIOL 通过降低神经的犬尿氨酸水平来促进学习

IF 10.5 1区生物学

Genes & development Pub Date : 2023-12-13 DOI: 10.1101/gad.350745.123

George A. Lemieux, Shinja Yoo, Lin Lin, Mihir Vohra, Kaveh Ashrafi

引用次数: 0

AI-assisted proofreading of RNA splicing 人工智能辅助校对 RNA 剪接

IF 10.5 1区生物学

Genes & development Pub Date : 2023-12-13 DOI: 10.1101/gad.351373.123

Ángel Guerra-Moreno, Juan Valcárcel

引用次数: 0

LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities LINE-1 基因逆转及其在癌症中的失调：对治疗机会的影响

IF 10.5 1区生物学

Genes & development Pub Date : 2023-12-13 DOI: 10.1101/gad.351051.123

Carlos Mendez-Dorantes, Kathleen H. Burns

引用次数: 0

Reviewers, Volume 37 (2023). 审稿人，第 37 卷（2023 年）。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-11-01

引用次数: 0

ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy. ATR抑制诱导错配修复缺陷细胞的合成致死性，并增强免疫疗法。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-10-01 Epub Date: 2023-11-06 DOI: 10.1101/gad.351084.123

Mingchao Wang, Xiaojuan Ran, Wendy Leung, Ajinkya Kawale, Sneha Saxena, Jian Ouyang, Parasvi S Patel, Yuting Dong, Tao Yin, Jian Shu, Robert T Manguso, Li Lan, Xiao-Fan Wang, Michael S Lawrence, Lee Zou

{"title":"ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.","authors":"Mingchao Wang, Xiaojuan Ran, Wendy Leung, Ajinkya Kawale, Sneha Saxena, Jian Ouyang, Parasvi S Patel, Yuting Dong, Tao Yin, Jian Shu, Robert T Manguso, Li Lan, Xiao-Fan Wang, Michael S Lawrence, Lee Zou","doi":"10.1101/gad.351084.123","DOIUrl":"10.1101/gad.351084.123","url":null,"abstract":"The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8+ T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71480457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels. MeCP2的一种新的致病性突变破坏了与蛋白质水平无关的染色质结合。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-10-01 Epub Date: 2023-10-27 DOI: 10.1101/gad.350733.123

Jian Zhou, Claudia Cattoglio, Yingyao Shao, Harini P Tirumala, Carlo Vetralla, Sameer S Bajikar, Yan Li, Hu Chen, Qi Wang, Zhenyu Wu, Bing Tang, Mahla Zahabiyon, Aleksandar Bajic, Xiangling Meng, Jack J Ferrie, Anel LaGrone, Ping Zhang, Jean J Kim, Jianrong Tang, Zhandong Liu, Xavier Darzacq, Nathaniel Heintz, Robert Tjian, Huda Y Zoghbi

{"title":"A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels.","authors":"Jian Zhou, Claudia Cattoglio, Yingyao Shao, Harini P Tirumala, Carlo Vetralla, Sameer S Bajikar, Yan Li, Hu Chen, Qi Wang, Zhenyu Wu, Bing Tang, Mahla Zahabiyon, Aleksandar Bajic, Xiangling Meng, Jack J Ferrie, Anel LaGrone, Ping Zhang, Jean J Kim, Jianrong Tang, Zhandong Liu, Xavier Darzacq, Nathaniel Heintz, Robert Tjian, Huda Y Zoghbi","doi":"10.1101/gad.350733.123","DOIUrl":"10.1101/gad.350733.123","url":null,"abstract":"Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61561951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0