Genes & development最新文献_第10页

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":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/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

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":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/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

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":null,"pages":null},"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

Distinct accessory roles of Arabidopsis VEL proteins in Polycomb silencing. 拟南芥VEL蛋白在多梳沉默中的不同辅助作用。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-09-01 Epub Date: 2023-09-21 DOI: 10.1101/gad.350814.123

Elsa Franco-Echevarría, Mathias Nielsen, Anna Schulten, Jitender Cheema, Tomos E Morgan, Mariann Bienz, Caroline Dean

{"title":"Distinct accessory roles of Arabidopsis VEL proteins in Polycomb silencing.","authors":"Elsa Franco-Echevarría, Mathias Nielsen, Anna Schulten, Jitender Cheema, Tomos E Morgan, Mariann Bienz, Caroline Dean","doi":"10.1101/gad.350814.123","DOIUrl":"10.1101/gad.350814.123","url":null,"abstract":"Polycomb repressive complex 2 (PRC2) mediates epigenetic silencing of target genes in animals and plants. In Arabidopsis, PRC2 is required for the cold-induced epigenetic silencing of the FLC floral repressor locus to align flowering with spring. During this process, PRC2 relies on VEL accessory factors, including the constitutively expressed VRN5 and the cold-induced VIN3. The VEL proteins are physically associated with PRC2, but their individual functions remain unclear. Here, we show an intimate association between recombinant VRN5 and multiple components within a reconstituted PRC2, dependent on a compact conformation of VRN5 central domains. Key residues mediating this compact conformation are conserved among VRN5 orthologs across the plant kingdom. In contrast, VIN3 interacts with VAL1, a transcriptional repressor that binds directly to FLC These associations differentially affect their role in H3K27me deposition: Both proteins are required for H3K27me3, but only VRN5 is necessary for H3K27me2. Although originally defined as vernalization regulators, VIN3 and VRN5 coassociate with many targets in the Arabidopsis genome that are modified with H3K27me3. Our work therefore reveals the distinct accessory roles for VEL proteins in conferring cold-induced silencing on FLC, with broad relevance for PRC2 targets generally.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7615239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41121626","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

Allelic chromatin structure precedes imprinted expression of Kcnk9 during neurogenesis. 在神经发生过程中，等位基因染色质结构先于Kcnk9的印迹表达。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-09-01 Epub Date: 2023-10-11 DOI: 10.1101/gad.350896.123

Daniel Loftus, Bongmin Bae, Courtney M Whilden, Amanda J Whipple

{"title":"Allelic chromatin structure precedes imprinted expression of Kcnk9 during neurogenesis.","authors":"Daniel Loftus, Bongmin Bae, Courtney M Whilden, Amanda J Whipple","doi":"10.1101/gad.350896.123","DOIUrl":"10.1101/gad.350896.123","url":null,"abstract":"Differences in chromatin state inherited from the parental gametes influence the regulation of maternal and paternal alleles in offspring. This phenomenon, known as genomic imprinting, results in genes preferentially transcribed from one parental allele. While local epigenetic factors such as DNA methylation are known to be important for the establishment of imprinted gene expression, less is known about the mechanisms by which differentially methylated regions (DMRs) lead to differences in allelic expression across broad stretches of chromatin. Allele-specific higher-order chromatin structure has been observed at multiple imprinted loci, consistent with the observation of allelic binding of the chromatin-organizing factor CTCF at multiple DMRs. However, whether allelic chromatin structure impacts allelic gene expression is not known for most imprinted loci. Here we characterize the mechanisms underlying brain-specific imprinted expression of the Peg13-Kcnk9 locus, an imprinted region associated with intellectual disability. We performed region capture Hi-C on mouse brains from reciprocal hybrid crosses and found imprinted higher-order chromatin structure caused by the allelic binding of CTCF to the Peg13 DMR. Using an in vitro neuron differentiation system, we showed that imprinted chromatin structure precedes imprinted expression at the locus. Additionally, activation of a distal enhancer induced imprinted expression of Kcnk9 in an allelic chromatin structure-dependent manner. This work provides a high-resolution map of imprinted chromatin structure and demonstrates that chromatin state established in early development can promote imprinted expression upon differentiation.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10620047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41198045","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

Folding makes an imprint. 折叠会留下印记。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-09-01 Epub Date: 2023-10-11 DOI: 10.1101/gad.351216.123

Stefan H Stricker

引用次数: 0

In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g. 严重急性呼吸系统综合征冠状病毒2型Nsp1诱导的mRNA切割的体外重建揭示了Nsp1的N-末端结构域和eIF3g的RRM结构域的关键作用。

IF 10.5 1区生物学

Genes & development Pub Date : 2023-09-01 Epub Date: 2023-10-11 DOI: 10.1101/gad.350829.123

Irina S Abaeva, Yani Arhab, Anna Miścicka, Christopher U T Hellen, Tatyana V Pestova

{"title":"In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g.","authors":"Irina S Abaeva, Yani Arhab, Anna Miścicka, Christopher U T Hellen, Tatyana V Pestova","doi":"10.1101/gad.350829.123","DOIUrl":"10.1101/gad.350829.123","url":null,"abstract":"SARS CoV-2 nonstructural protein 1 (Nsp1) is the major pathogenesis factor that inhibits host translation using a dual strategy of impairing initiation and inducing endonucleolytic cleavage of cellular mRNAs. To investigate the mechanism of cleavage, we reconstituted it in vitro on β-globin, EMCV IRES, and CrPV IRES mRNAs that use unrelated initiation mechanisms. In all instances, cleavage required Nsp1 and only canonical translational components (40S subunits and initiation factors), arguing against involvement of a putative cellular RNA endonuclease. Requirements for initiation factors differed for these mRNAs, reflecting their requirements for ribosomal attachment. Cleavage of CrPV IRES mRNA was supported by a minimal set of components consisting of 40S subunits and eIF3g's RRM domain. The cleavage site was located in the coding region 18 nt downstream from the mRNA entrance, indicating that cleavage occurs on the solvent side of the 40S subunit. Mutational analysis identified a positively charged surface on Nsp1's N-terminal domain (NTD) and a surface above the mRNA-binding channel on eIF3g's RRM domain that contain residues essential for cleavage. These residues were required for cleavage on all three mRNAs, highlighting general roles of the Nsp1 NTD and eIF3g's RRM domain in cleavage per se, irrespective of the mode of ribosomal attachment.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10620056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41198047","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