Genes & development最新文献_第5页

Chromosomal requirements for formation of multivalent human nucleoli. 形成多价人类核仁的染色体要求。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-21 DOI: 10.1101/gad.354012.126

Krystyna Giemza, Hazel Mangan, Brian McStay

引用次数: 0

Guardians of splicing: quality control mechanisms of snRNA variants. 剪接的守护者：snRNA变异的质量控制机制。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-21 DOI: 10.1101/gad.354115.126

Harihar Milaganur Mohan, Roy Parker

引用次数: 0

mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency. mTOR失活控制核糖体生物发生缺陷的适应性生存。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-10 DOI: 10.1101/gad.353708.126

Wenjun Fan, Hester Liu, Liling Yang, Niladri Sinha, Marco Catipovic, Daoyuan Dong, Hariharan Easawaran, Rachel Green, Marikki Laiho

{"title":"mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency.","authors":"Wenjun Fan, Hester Liu, Liling Yang, Niladri Sinha, Marco Catipovic, Daoyuan Dong, Hariharan Easawaran, Rachel Green, Marikki Laiho","doi":"10.1101/gad.353708.126","DOIUrl":"https://doi.org/10.1101/gad.353708.126","url":null,"abstract":"Ribosome biogenesis is a resource-consuming process that facilitates rapid growth and feeds uncontrolled, cancerous traits. Constraining ribosome biogenesis and protein translation has become a tenable therapeutic strategy for cancer. Yet, we do not know how cells that rely on high metabolic activity adapt and sustain their growth when deprived of their translational capacity. Conversely, stem cells and treatment-resistant cells persist under low metabolic states challenging their eradication. These are critical questions in cancer therapies. To delineate survival mechanisms that allow cancer cells to adapt to ribosome biogenesis defects, we conducted functional genomics screens during inhibition of RNA polymerase I. We identified that inactivation of mTOR enabled cell survival despite severe translational suppression. This was paradoxical as activation of mTOR is considered oncogenic by boosting ribosome biogenesis and cellular translational programs. We show that mTORC1 inhibition does neither restore rRNA synthesis nor ribosome biogenesis, but redistributes limited ribosomes from highly translated 5'TOP mRNAs to survival-essential transcripts. This mTOR inactivation-mediated prioritization of translational resources represents a minimal requirement for cell survival when translational capacity is compromised, which we term \"translational fitness.\" Our findings redefine the role of mTOR in cell survival and highlight the need for strategic targeting of translation regulation in cancer therapy.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706160","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

Mitotic MAX bookmarking drives MYC-dependent hypertranscription at TBP-bound promoters. 有丝分裂MAX书签在tbp结合启动子上驱动myc依赖性超转录。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-06 DOI: 10.1101/gad.354072.126

Inma Gonzalez, Lieng Taing, Almira Chervova, Pedro Escoll, Luis Altamirano-Pacheco, Alina Sommer, Teresa Urli, Maxim V C Greenberg, Véronique Legros, Guillaume Chevreux, Florian Mueller, Agnès Dubois, Pablo Navarro

{"title":"Mitotic MAX bookmarking drives MYC-dependent hypertranscription at TBP-bound promoters.","authors":"Inma Gonzalez, Lieng Taing, Almira Chervova, Pedro Escoll, Luis Altamirano-Pacheco, Alina Sommer, Teresa Urli, Maxim V C Greenberg, Véronique Legros, Guillaume Chevreux, Florian Mueller, Agnès Dubois, Pablo Navarro","doi":"10.1101/gad.354072.126","DOIUrl":"https://doi.org/10.1101/gad.354072.126","url":null,"abstract":"Faithful genome reactivation after mitosis is essential for cell identity, yet the mechanisms driving global postmitotic transcription remain unclear. Here, we show that the MYC oncogene and its obligate partner MAX drive a postmitotic hypertranscriptional state in mouse embryonic stem cells. Cell cycle-resolved single-cell RNA-seq in inducible Max -/- cells reveals that early G1 hypertranscription is strongly impaired without MAX. Mechanistically, MAX remains bound to thousands of promoters during mitosis, while MYC is largely excluded. Using high-temporal-resolution profiling, pharmacological inhibition of MYC/MAX, and acute MAX degradation at mitotic exit, we demonstrate that MAX mitotic binding triggers rapid MYC recruitment and transcriptional amplification of TBP-bound promoters by enhancing RNA polymerase II occupancy and efficient initiation and elongation. These findings redefine MYC/MAX as master regulators of gene regulatory inheritance across mitosis.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684220","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

Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes. 多个质量控制检查点保护小核RNA的生物发生，防止异常剪接体的组装。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-06 DOI: 10.1101/gad.353690.126

Tiantai Ma, Claire Huntington, Zhuoyi Song, Rea M Lardelli, Eric L Van Nostrand, Jens Lykke-Andersen

{"title":"Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes.","authors":"Tiantai Ma, Claire Huntington, Zhuoyi Song, Rea M Lardelli, Eric L Van Nostrand, Jens Lykke-Andersen","doi":"10.1101/gad.353690.126","DOIUrl":"10.1101/gad.353690.126","url":null,"abstract":"Defective small nuclear (sn)RNAs are produced from hundreds of human snRNA pseudogenes and mutant snRNA genes associated with human developmental disorders. Machineries that prevent defective snRNAs from disrupting pre-mRNA splicing remain poorly defined. Here, we identify multiple checkpoints in snRNA biogenesis monitored by quality control machineries that subject defective snRNAs to degradation and prevent their assembly into spliceosomes. We show that variant U1 snRNAs produced from human pseudogenes, some at rates approaching canonical snRNAs, are impaired in 3' cleavage and targeted for degradation by the NEXT-exosome while failures in subsequent protein assembly steps promote NEXT-exosome- or terminal uridylyl transferase 4/7-mediated degradation. These pathways also repress mutant snRNAs associated with human developmental disorders. Impeding snRNA quality control causes formation of aberrant spliceosomes and altered pre-mRNA splicing. These findings define checkpoints in snRNA biogenesis that safeguard pre-mRNA splicing and represent potential therapeutic targets for human disorders associated with snRNA mutations.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684147","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

The basic helix-loop-helix transcription factor TCF4 recruits the Mediator complex to activate gonadal genes and drive ovarian development. 基本的螺旋-环-螺旋转录因子TCF4招募中介复合物来激活性腺基因并驱动卵巢发育。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353245.125

Eleanore V O'Neil, Shannon M Dupont, Huan Liang, Rohit Singh, Blanche Capel

{"title":"The basic helix-loop-helix transcription factor TCF4 recruits the Mediator complex to activate gonadal genes and drive ovarian development.","authors":"Eleanore V O'Neil, Shannon M Dupont, Huan Liang, Rohit Singh, Blanche Capel","doi":"10.1101/gad.353245.125","DOIUrl":"10.1101/gad.353245.125","url":null,"abstract":"The bipotential gonad is the precursor to the ovary and testis. In mice, gonad differentiation is initiated by commitment of presupporting cells into testicular Sertoli cells or ovarian granulosa cells. While Sry drives testis differentiation, upstream drivers of ovary fate are unclear. We identified binding sites for basic helix-loop-helix (bHLH) transcription factors (TFs) upstream of granulosa genes and sought to investigate whether bHLH TFs regulate granulosa specification. bHLH transcription factor 4 (TCF4) was expressed in presupporting cells before sex determination. As development progressed, TCF4 was maintained in granulosa cells but lost in Sertoli cells. In Tcf4 STOP/STOP mutant mice lacking the TCF4 DNA-binding domain, FOXL2 was reduced in granulosa cells and nuclear morphology was altered. Mutant ovaries failed to undergo morphological changes similar to wild-type littermates. Meanwhile, Tcf4 STOP/STOP mutant testes appeared normal. We found that TCF4 binds the Mediator complex to regulate expression of gonadal genes (Wt1, Nr2f2) and granulosa-enriched genes including Jun and Fos In ex vivo gonad culture, inhibition of JUN activation led to decreased Wnt4 expression. These results support the hypothesis that TCF4 regulates an underlying gonadal program that primes the gonad toward a female fate and is silenced in Sertoli cells downstream from Sry.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1350-1365"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470049","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

TET1 noncatalytic activity shapes the chromatin landscape associated with de novo methylation establishment in the male germline. TET1非催化活性塑造了与雄性种系从头甲基化建立相关的染色质景观。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353483.125

Rexxi D Prasasya, Jean J Kim, Zhengfeng Liu, Rahul M Kohli, Marisa S Bartolomei

引用次数: 0

SMARCAL1 is a candidate therapeutic target for ALT-positive tumors. SMARCAL1是alt阳性肿瘤的候选治疗靶点。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353377.125

Angelo Taglialatela, Jina Lee, Benura Azeroglu, Xiao Chen, Maria Rosaria Dello Stritto, Antoine Gouge, Tomas Lama-Diaz, Alina Vaitsiankova, Giuseppe Leuzzi, Filemon Dela Cruz, Zahra F Khan, Andrew L Kung, Petr Cejka, Eros Lazzerini Denchi, Jaewon Min, Alberto Ciccia

{"title":"SMARCAL1 is a candidate therapeutic target for ALT-positive tumors.","authors":"Angelo Taglialatela, Jina Lee, Benura Azeroglu, Xiao Chen, Maria Rosaria Dello Stritto, Antoine Gouge, Tomas Lama-Diaz, Alina Vaitsiankova, Giuseppe Leuzzi, Filemon Dela Cruz, Zahra F Khan, Andrew L Kung, Petr Cejka, Eros Lazzerini Denchi, Jaewon Min, Alberto Ciccia","doi":"10.1101/gad.353377.125","DOIUrl":"10.1101/gad.353377.125","url":null,"abstract":"A significant subset of tumors, including >50% of osteosarcomas-an aggressive bone malignancy affecting children, adolescents, and young adults-relies on alternative lengthening of telomeres (ALT), a telomerase-independent, DNA repair-based mechanism for telomere elongation. The overall 5 year survival rate for osteosarcoma patients is ∼65%, underscoring the need to develop novel targeted therapies. Through the Cancer Dependency Map, we identified SMARCAL1, a DNA translocase previously shown to remodel stalled replication forks, as a top selective dependency factor in telomerase-negative tumors. Using a panel of ALT-positive and ALT-negative cancer cell lines, as well as osteosarcoma patient-derived xenograft cells, we confirmed that ALT-positive cells are uniquely sensitive to the loss of SMARCAL1, whose depletion exacerbates ALT-dependent phenotypes and telomeric DNA damage. Notably, we demonstrated that suppressing ALT abrogates their dependency on SMARCAL1. Mechanistically, we showed that SMARCAL1 loss leads to telomeric ssDNA accumulation in ALT-positive cells, dependent in part on DNA repriming mediated by the DNA primase/polymerase PRIMPOL. Moreover, SMARCAL1's ssDNA annealing activity counteracts DNA unwinding by the BLM helicase, limiting telomeric ssDNA accumulation and DNA damage in ALT-positive cells. Importantly, SMARCAL1 depletion induces senescence in ALT-positive cancer cells, rendering them susceptible to treatment with senolytic agents. Together, these findings establish SMARCAL1 as a key regulator of ALT metabolism and highlight SMARCAL1 as a promising therapeutic target for ALT-positive tumors.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1283-1303"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13431158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445719","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

LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development. 在肠神经系统发育过程中，LKB1作为神经元-胶质平衡的检查点。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353358.125

Anthony Lucas, Florence Appaix, Jordan Allard, Marie Mével-Aliset, Anca G Radu, Florence Fauvelle, Bertrand Favier, Alexei Grichine, Jochen Maurer, Pierre Hainaut, Laura Attardi, Marc Billaud, Sakina Torch, Chantal Thibert

{"title":"LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development.","authors":"Anthony Lucas, Florence Appaix, Jordan Allard, Marie Mével-Aliset, Anca G Radu, Florence Fauvelle, Bertrand Favier, Alexei Grichine, Jochen Maurer, Pierre Hainaut, Laura Attardi, Marc Billaud, Sakina Torch, Chantal Thibert","doi":"10.1101/gad.353358.125","DOIUrl":"https://doi.org/10.1101/gad.353358.125","url":null,"abstract":"How the energy status of enteric progenitors controls neurogliogenesis and the subsequent formation of the complex enteric nervous system (ENS) remains poorly understood. We previously showed that the tumor suppressor kinase LKB1 is essential for postnatal ENS maintenance through amino acid homeostasis. Here, we investigated LKB1's functions during embryonic ENS formation using a genetically engineered mouse model with conditional Lkb1 inactivation in neural crest progenitors during gut colonization. Using advanced 3D imaging techniques on cleared tissue including light sheet microscopy and adaptive optics confocal microscopy, we found that Lkb1 loss impairs early neuronal differentiation followed by progressive glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Notably, Lkb1 inactivation induced a transient upregulation of the glial stress marker S100β during gestation, suggestive of a reactive glial state preceding glial loss. Consistent with this response, Lkb1 loss elevated oxidative stress in the digestive tract and in neural crest progenitors and their glial derivatives, triggering DNA damage and p53 activation. Although p53 ablation rescued glial specification in vitro and glial maintenance in vivo, it only partially restored ENS architecture in vivo without rescuing enteric neuron numbers. Together, these findings establish LKB1 as a critical metabolic checkpoint governing neuronal-glial balance during ENS development and suggest that dysregulated LKB1 signaling may contribute to human enteric neurogliopathies.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"40 15-16","pages":"1227-1249"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669046","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

Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease. Capicua亚型的功能分化解释了神经系统疾病中组织易感性的差异。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-08-03 DOI: 10.1101/gad.353596.125

Hamin Lee, Esmeralda Villavicencio Gonzalez, Elias M Rivera, Mark A Durham, Ronald Richman, Elizabeth H-Y Chu, Kailey Xia, Hu Chen, Zhandong Liu, Surabi Veeraragavan, Binoy Shivanna, Huda Y Zoghbi

{"title":"Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.","authors":"Hamin Lee, Esmeralda Villavicencio Gonzalez, Elias M Rivera, Mark A Durham, Ronald Richman, Elizabeth H-Y Chu, Kailey Xia, Hu Chen, Zhandong Liu, Surabi Veeraragavan, Binoy Shivanna, Huda Y Zoghbi","doi":"10.1101/gad.353596.125","DOIUrl":"10.1101/gad.353596.125","url":null,"abstract":"Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid β production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or short (CIC-S) isoform. Loss of CIC-L led to cognitive deficits, whereas loss of CIC-S caused early postnatal lethality, phenocopying ATXN1 and ATXN1L knockout mice, respectively. Furthermore, CIC-L preferentially interacts with ATXN1, and CIC-S with ATXN1L. Our data underscore the importance of isoform-paralog interplay in studying regional vulnerability in neurodegenerative diseases.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1267-1282"},"PeriodicalIF":7.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535806","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