Genes & development最新文献_第10页

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":" ","pages":"929-943"},"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":" ","pages":"883-900"},"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

MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival. MYC乙酰化赖氨酸残基驱动致癌细胞转化，并调节细胞粘附无关生长和存活的选择性遗传程序。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-10-01 Epub Date: 2023-10-18 DOI: 10.1101/gad.350736.123

Matthew Hurd, Jeffrey Pino, Kay Jang, Michael M Allevato, Marina Vorontchikhina, Wataru Ichikawa, Yifan Zhao, Ryan Gates, Emily Villalpando, Michael J Hamilton, Francesco Faiola, Songqin Pan, Yue Qi, Yu-Wen Hung, Thomas Girke, David Ann, Victoria Seewaldt, Ernest Martinez

{"title":"MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.","authors":"Matthew Hurd, Jeffrey Pino, Kay Jang, Michael M Allevato, Marina Vorontchikhina, Wataru Ichikawa, Yifan Zhao, Ryan Gates, Emily Villalpando, Michael J Hamilton, Francesco Faiola, Songqin Pan, Yue Qi, Yu-Wen Hung, Thomas Girke, David Ann, Victoria Seewaldt, Ernest Martinez","doi":"10.1101/gad.350736.123","DOIUrl":"10.1101/gad.350736.123","url":null,"abstract":"The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"865-882"},"PeriodicalIF":10.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49676527","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

Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR. 微卫星不稳定癌症细胞中细胞命运的综合图谱支持WRN和ATR的双重靶向。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-10-01 Epub Date: 2023-11-06 DOI: 10.1101/gad.351085.123

Dali Zong, Natasha C Koussa, James A Cornwell, Ajith V Pankajam, Michael J Kruhlak, Nancy Wong, Raj Chari, Steven D Cappell, André Nussenzweig

{"title":"Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR.","authors":"Dali Zong, Natasha C Koussa, James A Cornwell, Ajith V Pankajam, Michael J Kruhlak, Nancy Wong, Raj Chari, Steven D Cappell, André Nussenzweig","doi":"10.1101/gad.351085.123","DOIUrl":"10.1101/gad.351085.123","url":null,"abstract":"Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN-knowledge that would be helpful for informing clinical development of WRN targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system in which the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We found that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we found no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low-dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provide the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggest that dual targeting of WRN and ATR might be a useful strategy for treating MSI-H cancers.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"913-928"},"PeriodicalIF":10.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71480466","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

Reorganization of lamina-associated domains in early mouse embryos is regulated by RNA polymerase II activity. 早期小鼠胚胎中薄层相关结构域的重组受RNA聚合酶II活性的调节。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-10-01 Epub Date: 2023-11-01 DOI: 10.1101/gad.350799.123

Mrinmoy Pal, Luis Altamirano-Pacheco, Tamas Schauer, Maria-Elena Torres-Padilla

引用次数: 0

Imaging the binding of MECP2 to DNA. 对MECP2与DNA的结合进行成像。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-10-01 Epub Date: 2023-11-01 DOI: 10.1101/gad.351285.123

Anne E West

引用次数: 0

Mesenchymal stromal cells as conductors of adipose tissue remodeling. 间充质基质细胞作为脂肪组织重塑的导体。

IF 7.5 1区生物学

Genes & development Pub Date : 2023-09-01 Epub Date: 2023-10-05 DOI: 10.1101/gad.351069.123

Jessica Cannavino, Rana K Gupta

引用次数: 0

Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Stromal衍生的NRG1能够在胰腺癌症中实现致癌KRAS旁路。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-09-01 Epub Date: 2023-09-29 DOI: 10.1101/gad.351037.123

Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A LaBella, Deepavali Chakravarti, Denise J Spring, Yan Xia, Ronald A DePinho

{"title":"Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer.","authors":"Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A LaBella, Deepavali Chakravarti, Denise J Spring, Yan Xia, Ronald A DePinho","doi":"10.1101/gad.351037.123","DOIUrl":"10.1101/gad.351037.123","url":null,"abstract":"Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitors in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"818-828"},"PeriodicalIF":10.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41120626","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