Pub Date : 2025-12-03DOI: 10.1016/j.molcel.2025.11.010
Ruhul Amin, Ngoc-Han Ha, Tinghu Qiu, Ronald Holewinski, Khiem C. Lam, Amélie Daugherty-Lopès, Huaitian Liu, Andy D. Tran, Maxwell P. Lee, Thorkell Andresson, Romina S. Goldszmid, Kent W. Hunter
{"title":"NAT10 promotes cancer metastasis by modulating p300/CBP activity through chromatin-associated tRNA","authors":"Ruhul Amin, Ngoc-Han Ha, Tinghu Qiu, Ronald Holewinski, Khiem C. Lam, Amélie Daugherty-Lopès, Huaitian Liu, Andy D. Tran, Maxwell P. Lee, Thorkell Andresson, Romina S. Goldszmid, Kent W. Hunter","doi":"10.1016/j.molcel.2025.11.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.010","url":null,"abstract":"","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"30 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657548","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}
Pub Date : 2025-12-01DOI: 10.1016/j.molcel.2025.11.006
Alexander J. Stuart, Kaori K. Takai, Railia R. Gabbasova, Henry Sanford, Ekaterina V. Vinogradova, Titia de Lange
Replicative senescence is a powerful tumor suppressor pathway that curbs proliferation of human cells when a few critically-short telomeres activate the DNA damage response (DDR). We show that ATM is the sole DDR kinase responsible for the induction and maintenance of replicative senescence and that ATM inhibition can induce normal cell divisions in senescent cells. Compared to non-physiological atmospheric (∼20%) oxygen, primary fibroblast cells grown at physiological (3%) oxygen were more tolerant to critically short telomeres, explaining their extended replicative lifespan. We show that this tolerance is due to attenuation of the ATM response to double-strand breaks (DSBs) and unprotected telomeres. Our data indicate that the reduced ATM response to DSBs at 3% oxygen is due to increased ROS, which induces disulfide crosslinked ATM dimers that do not respond to DSBs. This regulation of cellular lifespan through attenuation of ATM at physiological oxygen has implications for tumor suppression through telomere shortening.
{"title":"Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen","authors":"Alexander J. Stuart, Kaori K. Takai, Railia R. Gabbasova, Henry Sanford, Ekaterina V. Vinogradova, Titia de Lange","doi":"10.1016/j.molcel.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.006","url":null,"abstract":"Replicative senescence is a powerful tumor suppressor pathway that curbs proliferation of human cells when a few critically-short telomeres activate the DNA damage response (DDR). We show that ATM is the sole DDR kinase responsible for the induction and maintenance of replicative senescence and that ATM inhibition can induce normal cell divisions in senescent cells. Compared to non-physiological atmospheric (∼20%) oxygen, primary fibroblast cells grown at physiological (3%) oxygen were more tolerant to critically short telomeres, explaining their extended replicative lifespan. We show that this tolerance is due to attenuation of the ATM response to double-strand breaks (DSBs) and unprotected telomeres. Our data indicate that the reduced ATM response to DSBs at 3% oxygen is due to increased ROS, which induces disulfide crosslinked ATM dimers that do not respond to DSBs. This regulation of cellular lifespan through attenuation of ATM at physiological oxygen has implications for tumor suppression through telomere shortening.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651033","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}
Pub Date : 2025-12-01DOI: 10.1016/j.molcel.2025.11.008
Qilong Wang, Yuening Jiang, Meiyu Bi, Gang Wang, Yinan Xiao, Hailian Zhao, Yuhan Guo, Xinyu Li, Wei Yue, Na Zhang, Bingteng Xie, Yuanchao Xue, Hang Yin, Peng Zou, Mo Li
Proteomics is transforming medical sciences, but bridging isolated samples with intact in vivo microenvironments remains a major hurdle. We present an in vivo proteomic labeling (IVPL) platform built on a new substrate, Btn-Ph-3F, and engineered ascorbate peroxidase (APEX2)-EGFPf/f mice. Btn-Ph-3F shows high stability in organs possessing complex microenvironments, while APEX2-EGFPf/f mice readily cross with commercial Cre lines, enabling specific proteomic labeling for customized cell groups in distant organs. IVPL robustly profiles in situ proteomes of intestinal epithelium, mammary gland, and tumor-infiltrating Treg cells, and, critically, labels trace exogenous proteomes from patient-derived exosomes in live mice. We identify lactate dehydrogenase A-like 6A (LDHAL6A) as a persisting exosomal effector that promotes malignant programs in recipient cells. Inhibition of LDHAL6A combined with paclitaxel treatment markedly suppresses triple-negative breast cancer growth and metastasis. Collectively, our work not only establishes an advanced model for IVPL but also profiles ultimately exosomal actors in recipient organs for targeted therapy.
{"title":"In vivo proteomic labeling reveals diverse proteomes for therapeutic targets","authors":"Qilong Wang, Yuening Jiang, Meiyu Bi, Gang Wang, Yinan Xiao, Hailian Zhao, Yuhan Guo, Xinyu Li, Wei Yue, Na Zhang, Bingteng Xie, Yuanchao Xue, Hang Yin, Peng Zou, Mo Li","doi":"10.1016/j.molcel.2025.11.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.008","url":null,"abstract":"Proteomics is transforming medical sciences, but bridging isolated samples with intact <em>in vivo</em> microenvironments remains a major hurdle. We present an <em>in vivo</em> proteomic labeling (IVPL) platform built on a new substrate, Btn-Ph-3F, and engineered ascorbate peroxidase (APEX2)-EGFP<sup>f/f</sup> mice. Btn-Ph-3F shows high stability in organs possessing complex microenvironments, while APEX2-EGFP<sup>f/f</sup> mice readily cross with commercial Cre lines, enabling specific proteomic labeling for customized cell groups in distant organs. IVPL robustly profiles <em>in situ</em> proteomes of intestinal epithelium, mammary gland, and tumor-infiltrating T<sub>reg</sub> cells, and, critically, labels trace exogenous proteomes from patient-derived exosomes in live mice. We identify lactate dehydrogenase A-like 6A (LDHAL6A) as a persisting exosomal effector that promotes malignant programs in recipient cells. Inhibition of LDHAL6A combined with paclitaxel treatment markedly suppresses triple-negative breast cancer growth and metastasis. Collectively, our work not only establishes an advanced model for IVPL but also profiles ultimately exosomal actors in recipient organs for targeted therapy.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"17 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651034","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}
Pub Date : 2025-11-24DOI: 10.1016/j.molcel.2025.11.002
Annarita Miluzio, Alessandra Scagliola, Ivan Ferrari, Hasan Yilmaz, Giacomo D’Andrea, Laura Cassina, Stefania Oliveto, Sara Ricciardi, Alessandra Boletta, Stefano Biffo
Translation is made of initiation, elongation, and termination. The role of termination in relaying extracellular outputs to the translation machinery is unknown. We show, in mice, that the controlled recycling of ribosomes post-termination is a major checkpoint that integrates mitogenic signals and antiviral responses. In detail, the recycling of ribosomes at stop codons, maximal translation, and cellular proliferation strictly depend on eIF6 phosphorylation, both in vitro and in vivo. Lack of eIF6 phosphorylation, as observed during viral infection or prolonged starving, causes accumulation of ribosomes at stop codons and a massive translational remodeling. The outcome is a cellular status that we named RESt, for reversible energetic stop. RESt is marked by pro-survival and pro-inflammatory NF-κB signaling and a switch to respiration. Acute RESt is rescued by eIF6 phosphorylation, but chronic RESt invivo leads to senescence. Thus, the recycling rate of ribosomes post-termination is a physiologically controlled event impacting initiation.
{"title":"Recycling of ribosomes at stop codons drives the rate of translation and the transition from proliferation to RESt","authors":"Annarita Miluzio, Alessandra Scagliola, Ivan Ferrari, Hasan Yilmaz, Giacomo D’Andrea, Laura Cassina, Stefania Oliveto, Sara Ricciardi, Alessandra Boletta, Stefano Biffo","doi":"10.1016/j.molcel.2025.11.002","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.002","url":null,"abstract":"Translation is made of initiation, elongation, and termination. The role of termination in relaying extracellular outputs to the translation machinery is unknown. We show, in mice, that the controlled recycling of ribosomes post-termination is a major checkpoint that integrates mitogenic signals and antiviral responses. In detail, the recycling of ribosomes at stop codons, maximal translation, and cellular proliferation strictly depend on eIF6 phosphorylation, both <em>in vitro</em> and <em>in vivo</em>. Lack of eIF6 phosphorylation, as observed during viral infection or prolonged starving, causes accumulation of ribosomes at stop codons and a massive translational remodeling. The outcome is a cellular status that we named RESt, for reversible energetic stop. RESt is marked by pro-survival and pro-inflammatory NF-κB signaling and a switch to respiration. Acute RESt is rescued by eIF6 phosphorylation, but chronic RESt <em>in</em> <em>vivo</em> leads to senescence. Thus, the recycling rate of ribosomes post-termination is a physiologically controlled event impacting initiation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"16 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583755","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}
Pub Date : 2025-11-24DOI: 10.1016/j.molcel.2025.11.004
Mostafa Zedan, Alexandra P. Schürch, Stephanie Heinrich, Pablo A. Gómez-García, Sarah Khawaja, Léona Dörries, Karsten Weis
When cells encounter stress, they rapidly mount an adaptive response by switching from pro-growth to stress-responsive gene expression programs. How cells selectively silence pre-existing, pro-growth transcripts yet efficiently translate transcriptionally induced stress mRNA and whether these transcriptional and post-transcriptional responses are coordinated are poorly understood. Here, we show that following acute glucose withdrawal in S. cerevisiae, pre-existing mRNAs are not first degraded to halt protein synthesis, nor are they sequestered away in P-bodies. Rather, their translation is quickly repressed through a sequence-independent mechanism that differentiates between mRNAs produced before and after stress, followed by their decay. Transcriptional induction of endogenous transcripts and reporter mRNAs during stress is sufficient to escape translational repression, while induction prior to stress leads to repression. Our results reveal a timing-controlled coordination of the transcriptional and translational responses in the nucleus and cytoplasm, ensuring a rapid and wide-scale reprogramming of gene expression following environmental stress.
{"title":"Timing of transcription controls the selective translation of newly synthesized mRNAs during acute environmental stress","authors":"Mostafa Zedan, Alexandra P. Schürch, Stephanie Heinrich, Pablo A. Gómez-García, Sarah Khawaja, Léona Dörries, Karsten Weis","doi":"10.1016/j.molcel.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.004","url":null,"abstract":"When cells encounter stress, they rapidly mount an adaptive response by switching from pro-growth to stress-responsive gene expression programs. How cells selectively silence pre-existing, pro-growth transcripts yet efficiently translate transcriptionally induced stress mRNA and whether these transcriptional and post-transcriptional responses are coordinated are poorly understood. Here, we show that following acute glucose withdrawal in <em>S. cerevisiae</em>, pre-existing mRNAs are not first degraded to halt protein synthesis, nor are they sequestered away in P-bodies. Rather, their translation is quickly repressed through a sequence-independent mechanism that differentiates between mRNAs produced before and after stress, followed by their decay. Transcriptional induction of endogenous transcripts and reporter mRNAs during stress is sufficient to escape translational repression, while induction prior to stress leads to repression. Our results reveal a timing-controlled coordination of the transcriptional and translational responses in the nucleus and cytoplasm, ensuring a rapid and wide-scale reprogramming of gene expression following environmental stress.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"191 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583864","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}
While some ATP-dependent chromatin remodelers are negatively regulated by short tracts of DNA sequences (i.e., poly d(A) or GC-rich), the INO80 chromatin remodeler is regulated by DNA not readily identified by its sequence but rather by its physical properties. The underlying reason for these differences appears to be the unique mechanism by which INO80 mobilizes nucleosomes. We find that the INO80 chromatin remodeler mobilizes nucleosomes by displacing DNA from the histone octamer and creating DNA “bulges” that translocate around the octamer in a wave-like manner. Nucleosome movement is blocked by inflexible nucleosomal DNA that interferes with the initial formation of DNA bulges and is linked to INO80’s accurate positioning of nucleosomes at the +1 position of yeast gene promoters. Some of the interactions of the Arp5 subunit are lost when bound to inflexible DNA and may act as sensors to regulate INO80 remodeling in a DNA-shape-dependent manner.
{"title":"DNA bendability inside the nucleosome regulates INO80’s nucleosome positioning","authors":"Shagun Shukla, Mzwanele Ngubo, Somnath Paul, Franziska Kunert, Jim Persinger, Junwoo Lee, Karl-Peter Hopfner, Blaine Bartholomew","doi":"10.1016/j.molcel.2025.10.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.010","url":null,"abstract":"While some ATP-dependent chromatin remodelers are negatively regulated by short tracts of DNA sequences (i.e., poly d(A) or GC-rich), the INO80 chromatin remodeler is regulated by DNA not readily identified by its sequence but rather by its physical properties. The underlying reason for these differences appears to be the unique mechanism by which INO80 mobilizes nucleosomes. We find that the INO80 chromatin remodeler mobilizes nucleosomes by displacing DNA from the histone octamer and creating DNA “bulges” that translocate around the octamer in a wave-like manner. Nucleosome movement is blocked by inflexible nucleosomal DNA that interferes with the initial formation of DNA bulges and is linked to INO80’s accurate positioning of nucleosomes at the +1 position of yeast gene promoters. Some of the interactions of the Arp5 subunit are lost when bound to inflexible DNA and may act as sensors to regulate INO80 remodeling in a DNA-shape-dependent manner.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"6 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583751","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}
Pub Date : 2025-11-24DOI: 10.1016/j.molcel.2025.11.003
Hendrik Glauninger, Jared A.M. Bard, Caitlin J. Wong Hickernell, Karen M. Velez, Edo M. Airoldi, Weihan Li, Robert H. Singer, Sneha Paul, Jingyi Fei, Tobin R. Sosnick, Edward W.J. Wallace, D. Allan Drummond
Stress-induced messenger ribonucleoprotein (mRNP) condensation is conserved across eukaryotes, resulting in stress granule formation under intense stresses, yet the mRNA composition and function of these condensates remain unclear. Exposure of ribosome-free mRNA following stress is thought to cause condensation and stress granule formation through mRNA-sequence-dependent interactions, leading to disproportionate condensation of long mRNAs. Here, we show that, by contrast, virtually all mRNAs condense in response to multiple stresses in budding yeast with minor length dependence and often without stress granule formation. New transcripts escape mRNP condensation, enabling their selective translation. Inhibiting translation initiation causes formation of mRNP condensates distinct from stress granules and processing bodies (P bodies), and these translation-initiation-inhibited condensates (TIICs) are omnipresent, even in unstressed cells. Stress-induced mRNAs are excluded from TIICs due to the timing of their expression, indicating determinants of escape that are independent of sequence. Together, our results reveal a previously undetected level of translation-linked molecular organization and stress-responsive regulation.
{"title":"Transcriptome-wide mRNP condensation precedes stress granule formation and excludes new mRNAs","authors":"Hendrik Glauninger, Jared A.M. Bard, Caitlin J. Wong Hickernell, Karen M. Velez, Edo M. Airoldi, Weihan Li, Robert H. Singer, Sneha Paul, Jingyi Fei, Tobin R. Sosnick, Edward W.J. Wallace, D. Allan Drummond","doi":"10.1016/j.molcel.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.003","url":null,"abstract":"Stress-induced messenger ribonucleoprotein (mRNP) condensation is conserved across eukaryotes, resulting in stress granule formation under intense stresses, yet the mRNA composition and function of these condensates remain unclear. Exposure of ribosome-free mRNA following stress is thought to cause condensation and stress granule formation through mRNA-sequence-dependent interactions, leading to disproportionate condensation of long mRNAs. Here, we show that, by contrast, virtually all mRNAs condense in response to multiple stresses in budding yeast with minor length dependence and often without stress granule formation. New transcripts escape mRNP condensation, enabling their selective translation. Inhibiting translation initiation causes formation of mRNP condensates distinct from stress granules and processing bodies (P bodies), and these translation-initiation-inhibited condensates (TIICs) are omnipresent, even in unstressed cells. Stress-induced mRNAs are excluded from TIICs due to the timing of their expression, indicating determinants of escape that are independent of sequence. Together, our results reveal a previously undetected level of translation-linked molecular organization and stress-responsive regulation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"32 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583761","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}
Lariat RNAs, generated as byproducts of RNA splicing from excised introns, must be removed. RNA debranching enzyme (DBR1) is the core factor responsible for lariat RNA removal. However, the mechanism by which DBR1 debranches lariat RNAs remains unclear. Here, we demonstrate that six ALBA (acetylation lowers binding affinity) proteins interact with DBR1 to enhance its debranching activity and facilitate DBR1’s accessibility to lariat RNAs, thereby promoting lariat RNA turnover. Similar to dbr1, alba mutants exhibit pleiotropic developmental defects and accumulate lariat RNAs. ALBAs bind to lariat RNAs via their C-terminal Arg-Gly-Gly/Arg-Gly (RGG/RG)-rich repeats and assist DBR1 in binding to these RNAs. The N-terminal ALBA domain mediates the interaction with DBR1 and enhances its enzymatic activity. Cold stress induces lariat RNA accumulation by attenuating the ALBA-DBR1 interaction, which in turn reduces the induction of cold-responsive genes by impairing their transcription. Together, these findings uncover that lariat RNA turnover requires ALBA proteins.
{"title":"Debranching enzyme DBR1-mediated lariat RNA turnover requires ALBA proteins in Arabidopsis","authors":"Haoran Ge, Qi Tang, Jingjing Wu, Xiaotuo Zhang, Yuxuan Li, Weiqaing Qian, Jinbiao Ma, Binglian Zheng","doi":"10.1016/j.molcel.2025.10.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.021","url":null,"abstract":"Lariat RNAs, generated as byproducts of RNA splicing from excised introns, must be removed. RNA debranching enzyme (DBR1) is the core factor responsible for lariat RNA removal. However, the mechanism by which DBR1 debranches lariat RNAs remains unclear. Here, we demonstrate that six ALBA (acetylation lowers binding affinity) proteins interact with DBR1 to enhance its debranching activity and facilitate DBR1’s accessibility to lariat RNAs, thereby promoting lariat RNA turnover. Similar to <em>dbr1</em>, <em>alba</em> mutants exhibit pleiotropic developmental defects and accumulate lariat RNAs. ALBAs bind to lariat RNAs via their C-terminal Arg-Gly-Gly/Arg-Gly (RGG/RG)-rich repeats and assist DBR1 in binding to these RNAs. The N-terminal ALBA domain mediates the interaction with DBR1 and enhances its enzymatic activity. Cold stress induces lariat RNA accumulation by attenuating the ALBA-DBR1 interaction, which in turn reduces the induction of cold-responsive genes by impairing their transcription. Together, these findings uncover that lariat RNA turnover requires ALBA proteins.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554807","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}
Pub Date : 2025-11-20DOI: 10.1016/j.molcel.2025.10.027
Benjamin Le Bozec, Laure Guitton-Sert, Sarah Collins, Anne-Laure Finoux, Charlotte Payrault, Emmanuelle Guillou, Marion Aguirrebengoa, Vanessa Dougados, Virginie Jouffret, Jessica Frison, Romane Carette, Vincent Rocher, Coline Arnould, Aude Guénolé, Ikrame Lazar, Aline Marnef, Philippe Frit, Patrick Calsou, Thomas Mangeat, Nadine Puget, Gaëlle Legube
Repair of DNA double-strand breaks (DSBs) produced in transcriptionally active chromatin occurs through a poorly characterized pathway called transcription-coupled DSB repair (TC-DSBR). Here, using a screening approach scoring multiple outputs in human cells, we identified proteins from the PERIOD complex, ensuring circadian oscillations, as previously unknown TC-DSBR players. We show that PER2 is recruited at TC-DSBs and contributes to their targeting to the nuclear envelope (NE), where SUN1 and the nuclear pore complex (NPC) act as docking sites. TC-DSB anchoring at the NE fosters RAD51 assembly and prevents DSB clustering and translocations. In agreement, the circadian clock regulates TC-DSB targeting to the NE, RAD51 assembly, and DSB clustering. Our study shows a direct link between the circadian rhythm and the response to DSBs in transcribed genes, opening strategies for chrono-chemotherapies based on topoisomerase poisons that induce DSBs in active loci.
{"title":"Circadian PERIOD proteins regulate TC-DSB repair through anchoring to the nuclear envelope","authors":"Benjamin Le Bozec, Laure Guitton-Sert, Sarah Collins, Anne-Laure Finoux, Charlotte Payrault, Emmanuelle Guillou, Marion Aguirrebengoa, Vanessa Dougados, Virginie Jouffret, Jessica Frison, Romane Carette, Vincent Rocher, Coline Arnould, Aude Guénolé, Ikrame Lazar, Aline Marnef, Philippe Frit, Patrick Calsou, Thomas Mangeat, Nadine Puget, Gaëlle Legube","doi":"10.1016/j.molcel.2025.10.027","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.027","url":null,"abstract":"Repair of DNA double-strand breaks (DSBs) produced in transcriptionally active chromatin occurs through a poorly characterized pathway called transcription-coupled DSB repair (TC-DSBR). Here, using a screening approach scoring multiple outputs in human cells, we identified proteins from the PERIOD complex, ensuring circadian oscillations, as previously unknown TC-DSBR players. We show that PER2 is recruited at TC-DSBs and contributes to their targeting to the nuclear envelope (NE), where SUN1 and the nuclear pore complex (NPC) act as docking sites. TC-DSB anchoring at the NE fosters RAD51 assembly and prevents DSB clustering and translocations. In agreement, the circadian clock regulates TC-DSB targeting to the NE, RAD51 assembly, and DSB clustering. Our study shows a direct link between the circadian rhythm and the response to DSBs in transcribed genes, opening strategies for chrono-chemotherapies based on topoisomerase poisons that induce DSBs in active loci.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"11 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554801","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}
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