Pub Date : 2025-12-04DOI: 10.1016/j.molcel.2025.11.012
Qi-Xiang Ma, Miao Yin, Qun-Ying Lei
How the oncogenic and tumor-suppressor roles of orphan nuclear receptor 4A1 (NR4A1) are balanced remains unclear. In this issue of Molecular Cell, Cai et al.1 report that a pyrimidine metabolite—UMP—acts as an endogenous regulator of NR4A1 by directly binding to abrogate its suppressive effect on gastric cancer development.
孤儿核受体4A1 （NR4A1）的致癌和抑瘤作用是如何平衡的尚不清楚。Cai et al.1在本期Molecular Cell中报道了一种嘧啶代谢物- ump -通过直接结合NR4A1作为内源性调节剂，从而消除其对胃癌发展的抑制作用。
{"title":"A nucleotide regulates NR4A1 status in gastric cancer","authors":"Qi-Xiang Ma, Miao Yin, Qun-Ying Lei","doi":"10.1016/j.molcel.2025.11.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.012","url":null,"abstract":"How the oncogenic and tumor-suppressor roles of orphan nuclear receptor 4A1 (NR4A1) are balanced remains unclear. In this issue of <em>Molecular Cell</em>, Cai et al.<span><span><sup>1</sup></span></span> report that a pyrimidine metabolite—UMP—acts as an endogenous regulator of NR4A1 by directly binding to abrogate its suppressive effect on gastric cancer development.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"26 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673650","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 : 2025-12-03DOI: 10.1016/j.molcel.2025.11.013
Andreas Aufschnaiter, Teak-Jung Oh, Andrew Oberst
Cells can die via any of several forms of regulated cell death (RCD), including apoptosis, pyroptosis, and necroptosis. We now appreciate that there is substantial crosstalk between them, allowing for a high degree of plasticity downstream of cell death triggers. Understanding this is essential to delineate roles of RCD in development, homeostasis, tumor biology, and immunity; however, this crosstalk can make the fate of individual cells difficult to visualize. Here, we present a conceptual framework that builds on Waddington’s landscape model of lineage commitment. On the landscape of RCD, live cells begin atop a “mountain,” from which they roll down via “valleys” representing different cell death programs, potentially being diverted or even raised back to the summit by regulators of these processes. While acknowledging that, like any conceptual framework, this visualization is imperfect, we hope it presents a succinct approach to understand the complexities and interconnections of cell death regulation.
{"title":"The landscape of regulated cell death: It’s all downhill from here","authors":"Andreas Aufschnaiter, Teak-Jung Oh, Andrew Oberst","doi":"10.1016/j.molcel.2025.11.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.013","url":null,"abstract":"Cells can die via any of several forms of regulated cell death (RCD), including apoptosis, pyroptosis, and necroptosis. We now appreciate that there is substantial crosstalk between them, allowing for a high degree of plasticity downstream of cell death triggers. Understanding this is essential to delineate roles of RCD in development, homeostasis, tumor biology, and immunity; however, this crosstalk can make the fate of individual cells difficult to visualize. Here, we present a conceptual framework that builds on Waddington’s landscape model of lineage commitment. On the landscape of RCD, live cells begin atop a “mountain,” from which they roll down via “valleys” representing different cell death programs, potentially being diverted or even raised back to the summit by regulators of these processes. While acknowledging that, like any conceptual framework, this visualization is imperfect, we hope it presents a succinct approach to understand the complexities and interconnections of cell death regulation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"75 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657546","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 : 2025-12-03DOI: 10.1016/j.molcel.2025.11.009
Shashank Srivastava, Daniela Samaniego-Castruita, Shubhi Srivastava, Sakshi Khurana, Jalees Rehman, Vipul Shukla, Issam Ben-Sahra, Daniel R. Foltz
Chromatin formation requires both an adequate nucleotide supply and histone availability. Newly synthesized histones are escorted by histone chaperones that mediate their orderly transfer from ribosomes to DNA. While nucleotide and histone synthesis are the two major biosynthetic processes required for chromatin assembly, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs), which catalyze the first and rate-limiting step in nucleotide biosynthesis, form a complex with PRPS-associated proteins (PRPSAPs). Using a rapid degron system in multiple human cell lines, we show that PRPS enzymes, together with PRPSAPs, play a key role in early histone maturation independent of their nucleotide biosynthetic function. Depletion of either PRPS1 or PRPSAP1 limits histone availability and disrupts chromatin assembly. These findings reveal a previously unrecognized synchrony between nucleotide metabolism and chromatin regulation, providing insight into how nucleotide production and histone deposition are coordinated.
{"title":"Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation","authors":"Shashank Srivastava, Daniela Samaniego-Castruita, Shubhi Srivastava, Sakshi Khurana, Jalees Rehman, Vipul Shukla, Issam Ben-Sahra, Daniel R. Foltz","doi":"10.1016/j.molcel.2025.11.009","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.009","url":null,"abstract":"Chromatin formation requires both an adequate nucleotide supply and histone availability. Newly synthesized histones are escorted by histone chaperones that mediate their orderly transfer from ribosomes to DNA. While nucleotide and histone synthesis are the two major biosynthetic processes required for chromatin assembly, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs), which catalyze the first and rate-limiting step in nucleotide biosynthesis, form a complex with PRPS-associated proteins (PRPSAPs). Using a rapid degron system in multiple human cell lines, we show that PRPS enzymes, together with PRPSAPs, play a key role in early histone maturation independent of their nucleotide biosynthetic function. Depletion of either PRPS1 or PRPSAP1 limits histone availability and disrupts chromatin assembly. These findings reveal a previously unrecognized synchrony between nucleotide metabolism and chromatin regulation, providing insight into how nucleotide production and histone deposition are coordinated.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"120 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658090","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 : 2025-12-03DOI: 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}
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