Pub Date : 2024-11-14DOI: 10.1016/j.molcel.2024.10.028
Junya Ito, Toshitaka Nakamura, Takashi Toyama, Deng Chen, Carsten Berndt, Gereon Poschmann, André Santos Dias Mourão, Sebastian Doll, Mirai Suzuki, Weijia Zhang, Jiashuo Zheng, Dietrich Trümbach, Naoya Yamada, Koya Ono, Masana Yazaki, Yasutaka Kawai, Mieko Arisawa, Yusuke Ohsaki, Hitoshi Shirakawa, Adam Wahida, Marcus Conrad
Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in Prdx6-deficient mouse brains and increased sensitivity to ferroptosis in PRDX6-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity.
{"title":"PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization","authors":"Junya Ito, Toshitaka Nakamura, Takashi Toyama, Deng Chen, Carsten Berndt, Gereon Poschmann, André Santos Dias Mourão, Sebastian Doll, Mirai Suzuki, Weijia Zhang, Jiashuo Zheng, Dietrich Trümbach, Naoya Yamada, Koya Ono, Masana Yazaki, Yasutaka Kawai, Mieko Arisawa, Yusuke Ohsaki, Hitoshi Shirakawa, Adam Wahida, Marcus Conrad","doi":"10.1016/j.molcel.2024.10.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.028","url":null,"abstract":"Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in <em>Prdx6</em>-deficient mouse brains and increased sensitivity to ferroptosis in <em>PRDX6</em>-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"128 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610583","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 : 2024-11-14DOI: 10.1016/j.molcel.2024.10.030
Anisha R. Ramadhin, Shun-Hsiao Lee, Di Zhou, Anita Salmazo, Camila Gonzalo-Hansen, Marjolein van Sluis, Cindy M.A. Blom, Roel C. Janssens, Anja Raams, Dick Dekkers, Karel Bezstarosti, Dea Slade, Wim Vermeulen, Alex Pines, Jeroen A.A. Demmers, Carrie Bernecky, Titia K. Sixma, Jurgen A. Marteijn
Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II). TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which recruits the CRL4CSA ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4CSA serves as a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment. However, the precise regulatory mechanisms of CRL4CSA activity and TFIIH recruitment remain elusive. Here, we reveal human serine/threonine-protein kinase 19 (STK19) as a TC-NER factor, which is essential for correct DNA damage removal and subsequent transcription restart. Cryogenic electron microscopy (cryo-EM) studies demonstrate that STK19 is an integral part of the RNA Pol II-TC-NER complex, bridging CSA, UVSSA, RNA Pol II, and downstream DNA. STK19 stimulates TC-NER complex stability and CRL4CSA activity, resulting in efficient RNA Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core TC-NER component.
转录耦合核苷酸切除修复（TC-NER）可有效消除阻碍 RNA 聚合酶 II（RNA Pol II）进行基因转录的 DNA 损伤。TC-NER 由 CSB 识别损伤停滞的 RNA Pol II 启动，CSB 会招募 CRL4CSA 泛素连接酶和 UVSSA。CRL4CSA 在 RPB1-K1268 处的 RNA Pol II 泛素化是一个关键的 TC-NER 检查点，可控制 RNA Pol II 的稳定性，并通过 TFIIH 招募启动 DNA 损伤切除。然而，CRL4CSA 活性和 TFIIH 招募的精确调控机制仍然难以捉摸。在这里，我们揭示了人类丝氨酸/苏氨酸蛋白激酶19（STK19）作为TC-NER因子，对正确的DNA损伤切除和随后的转录重启至关重要。低温电子显微镜（cryo-EM）研究表明，STK19是RNA Pol II-TC-NER复合物的一个组成部分，它连接着CSA、UVSSA、RNA Pol II和下游DNA。STK19 能刺激 TC-NER 复合物的稳定性和 CRL4CSA 的活性，从而高效地实现 RNA Pol II 泛素化和正确的 UVSSA 与 TFIIH 结合。这些发现强调了 STK19 作为 TC-NER 核心部件的关键作用。
{"title":"STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment","authors":"Anisha R. Ramadhin, Shun-Hsiao Lee, Di Zhou, Anita Salmazo, Camila Gonzalo-Hansen, Marjolein van Sluis, Cindy M.A. Blom, Roel C. Janssens, Anja Raams, Dick Dekkers, Karel Bezstarosti, Dea Slade, Wim Vermeulen, Alex Pines, Jeroen A.A. Demmers, Carrie Bernecky, Titia K. Sixma, Jurgen A. Marteijn","doi":"10.1016/j.molcel.2024.10.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.030","url":null,"abstract":"Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II). TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which recruits the CRL4<sup>CSA</sup> ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4<sup>CSA</sup> serves as a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment. However, the precise regulatory mechanisms of CRL4<sup>CSA</sup> activity and TFIIH recruitment remain elusive. Here, we reveal human serine/threonine-protein kinase 19 (STK19) as a TC-NER factor, which is essential for correct DNA damage removal and subsequent transcription restart. Cryogenic electron microscopy (cryo-EM) studies demonstrate that STK19 is an integral part of the RNA Pol II-TC-NER complex, bridging CSA, UVSSA, RNA Pol II, and downstream DNA. STK19 stimulates TC-NER complex stability and CRL4<sup>CSA</sup> activity, resulting in efficient RNA Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core TC-NER component.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"87 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610573","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 : 2024-11-14DOI: 10.1016/j.molcel.2024.10.027
Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara N. Xavier da Silva, Ancely Ferreira dos Santos, Tasneem Cheytan, Florencio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela Peglow Pinz, Isadora Medeiros, Thais Satie Iijima, Thiago Geronimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein-Seetharaman, José Pedro Friedmann Angeli
Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H2SePO3−), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation.
{"title":"PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance","authors":"Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara N. Xavier da Silva, Ancely Ferreira dos Santos, Tasneem Cheytan, Florencio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela Peglow Pinz, Isadora Medeiros, Thais Satie Iijima, Thiago Geronimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein-Seetharaman, José Pedro Friedmann Angeli","doi":"10.1016/j.molcel.2024.10.027","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.027","url":null,"abstract":"Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H<sub>2</sub>SePO<sub>3</sub><sup>−</sup>), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"98 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610081","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 : 2024-11-12DOI: 10.1016/j.molcel.2024.10.024
Marie-France Langelier, Manija Mirhasan, Karine Gilbert, Aleksandr Sverzhinksy, Alexandra Furtos, John M. Pascal
PARP enzymes transfer ADP-ribose from NAD+ onto proteins as a covalent modification that regulates multiple aspects of cell biology. Here, we identify an undiscovered catalytic activity for human PARP1: de novo generation of free PAR molecules that are not attached to proteins. Free PAR production arises when a molecule of NAD+ or ADP-ribose docks in the PARP1 acceptor site and attaches to an NAD+ molecule bound to the donor site, releasing nicotinamide and initiating ADP-ribose chains that emanate from NAD+/ADP-ribose rather than protein. Free PAR is also produced by human PARP2 and the PARP enzyme Tankyrase. We demonstrate that free PAR in cells is generated mostly by PARP1 de novo synthesis activity rather than by PAR-degrading enzymes PAR glycohydrolase (PARG), ARH3, and TARG1 releasing PAR from protein. The coincident production of free PAR and protein-linked modifications alters models for PAR signaling and broadens the scope of PARP enzyme signaling capacity.
PARP 酶将 NAD+ 中的 ADP 核糖转移到蛋白质上，作为一种共价修饰，调节着细胞生物学的多个方面。在这里，我们发现了人类 PARP1 的一种未被发现的催化活性：从头生成未附着在蛋白质上的游离 PAR 分子。当一个 NAD+ 分子或 ADP-ribose 分子与 PARP1 受体位点对接，并与结合在供体位点的 NAD+ 分子结合，释放出烟酰胺并启动由 NAD+/ADP-ribose 而不是蛋白质产生的 ADP-ribose 链时，就会产生游离 PAR。人类 PARP2 和 PARP 酶 Tankyrase 也会产生游离 PAR。我们证明，细胞中的游离 PAR 主要是由 PARP1 从头合成活性产生的，而不是由 PAR 糖水解酶（PARG）、ARH3 和 TARG1 从蛋白质中释放 PAR 而产生的。游离 PAR 和蛋白质连接修饰的同时产生改变了 PAR 信号转导的模型，扩大了 PARP 酶信号转导能力的范围。
{"title":"PARP enzyme de novo synthesis of protein-free poly(ADP-ribose)","authors":"Marie-France Langelier, Manija Mirhasan, Karine Gilbert, Aleksandr Sverzhinksy, Alexandra Furtos, John M. Pascal","doi":"10.1016/j.molcel.2024.10.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.024","url":null,"abstract":"PARP enzymes transfer ADP-ribose from NAD<sup>+</sup> onto proteins as a covalent modification that regulates multiple aspects of cell biology. Here, we identify an undiscovered catalytic activity for human PARP1: <em>de novo</em> generation of free PAR molecules that are not attached to proteins. Free PAR production arises when a molecule of NAD<sup>+</sup> or ADP-ribose docks in the PARP1 acceptor site and attaches to an NAD<sup>+</sup> molecule bound to the donor site, releasing nicotinamide and initiating ADP-ribose chains that emanate from NAD<sup>+</sup>/ADP-ribose rather than protein. Free PAR is also produced by human PARP2 and the PARP enzyme Tankyrase. We demonstrate that free PAR in cells is generated mostly by PARP1 <em>de novo</em> synthesis activity rather than by PAR-degrading enzymes PAR glycohydrolase (PARG), ARH3, and TARG1 releasing PAR from protein. The coincident production of free PAR and protein-linked modifications alters models for PAR signaling and broadens the scope of PARP enzyme signaling capacity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"63 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599536","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 : 2024-11-12DOI: 10.1016/j.molcel.2024.10.023
Jan Dreyer, Giulia Ricci, Jeroen van den Berg, Vivek Bhardwaj, Janina Funk, Claire Armstrong, Vincent van Batenburg, Chance Sine, Michael A. VanInsberghe, Rinskje B. Tjeerdsma, Richard Marsman, Imke K. Mandemaker, Simone di Sanzo, Juliette Costantini, Stefano G. Manzo, Alva Biran, Claire Burny, Marcel A.T.M. van Vugt, Moritz Völker-Albert, Anja Groth, Francesca Mattiroli
Long-term perturbation of de novo chromatin assembly during DNA replication has profound effects on epigenome maintenance and cell fate. The early mechanistic origin of these defects is unknown. Here, we combine acute degradation of chromatin assembly factor 1 (CAF-1), a key player in de novo chromatin assembly, with single-cell genomics, quantitative proteomics, and live microscopy to uncover these initiating mechanisms in human cells. CAF-1 loss immediately slows down DNA replication speed and renders nascent DNA hyper-accessible. A rapid cellular response, distinct from canonical DNA damage signaling, is triggered and lowers histone mRNAs. In turn, histone variants’ usage and their modifications are altered, limiting transcriptional fidelity and delaying chromatin maturation within a single S-phase. This multi-level response induces a p53-dependent cell-cycle arrest after mitosis. Our work reveals the immediate consequences of defective de novo chromatin assembly during DNA replication, indicating how at later times the epigenome and cell fate can be altered.
DNA 复制过程中染色质从头组装的长期扰动会对表观基因组的维持和细胞命运产生深远影响。这些缺陷的早期机理起源尚不清楚。在这里，我们将染色质组装因子 1（CAF-1）（染色质从头组装的关键角色）的急性降解与单细胞基因组学、定量蛋白质组学和活体显微镜相结合，揭示了人类细胞中的这些启动机制。CAF-1的缺失会立即降低DNA复制速度，并使新生DNA变得极易获取。一种有别于典型 DNA 损伤信号的快速细胞反应被触发并降低组蛋白 mRNA。反过来，组蛋白变体的使用及其修饰也发生了改变，从而限制了转录的保真度，并推迟了染色质在单个 S 期的成熟。这种多级反应诱导了有丝分裂后依赖 p53 的细胞周期停滞。我们的研究揭示了DNA复制过程中染色质从头组装缺陷的直接后果，并指出了表观基因组和细胞命运在后期如何发生改变。
{"title":"Acute multi-level response to defective de novo chromatin assembly in S-phase","authors":"Jan Dreyer, Giulia Ricci, Jeroen van den Berg, Vivek Bhardwaj, Janina Funk, Claire Armstrong, Vincent van Batenburg, Chance Sine, Michael A. VanInsberghe, Rinskje B. Tjeerdsma, Richard Marsman, Imke K. Mandemaker, Simone di Sanzo, Juliette Costantini, Stefano G. Manzo, Alva Biran, Claire Burny, Marcel A.T.M. van Vugt, Moritz Völker-Albert, Anja Groth, Francesca Mattiroli","doi":"10.1016/j.molcel.2024.10.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.023","url":null,"abstract":"Long-term perturbation of <em>de novo</em> chromatin assembly during DNA replication has profound effects on epigenome maintenance and cell fate. The early mechanistic origin of these defects is unknown. Here, we combine acute degradation of chromatin assembly factor 1 (CAF-1), a key player in <em>de novo</em> chromatin assembly, with single-cell genomics, quantitative proteomics, and live microscopy to uncover these initiating mechanisms in human cells. CAF-1 loss immediately slows down DNA replication speed and renders nascent DNA hyper-accessible. A rapid cellular response, distinct from canonical DNA damage signaling, is triggered and lowers histone mRNAs. In turn, histone variants’ usage and their modifications are altered, limiting transcriptional fidelity and delaying chromatin maturation within a single S-phase. This multi-level response induces a p53-dependent cell-cycle arrest after mitosis. Our work reveals the immediate consequences of defective <em>de novo</em> chromatin assembly during DNA replication, indicating how at later times the epigenome and cell fate can be altered.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"31 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599537","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 : 2024-11-11DOI: 10.1016/j.molcel.2024.10.020
Jinli Wang, Nikole L. Fendler, Ashutosh Shukla, Shwu-Yuan Wu, Ashwini Challa, Jeon Lee, Lukasz A. Joachimiak, John D. Minna, Cheng-Ming Chiang, Seychelle M. Vos, Iván D’Orso
The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription. Second, ARF targets the RUNX family transcription factor 1 (RUNX1) to selectively tune gene transcription. Consistently, ARF loss triggers RUNX1- and PAF1c-dependent transcriptional activation of pro-growth ligands (growth differentiation factor/bone morphogenetic protein [GDF/BMP]), promoting a cell-intrinsic GDF/BMP-Smad1/5 axis that aberrantly induce cell growth. Notably, pharmacologic inactivation of GDF/BMP signaling and genetic perturbation of RUNX1 significantly attenuate cell proliferation mediated by dual p53 and ARF loss, offering therapeutic utility. Our data underscore the significance of selective ARF-mediated tumor-suppressive functions through a universal transcriptional regulator.
{"title":"ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss","authors":"Jinli Wang, Nikole L. Fendler, Ashutosh Shukla, Shwu-Yuan Wu, Ashwini Challa, Jeon Lee, Lukasz A. Joachimiak, John D. Minna, Cheng-Ming Chiang, Seychelle M. Vos, Iván D’Orso","doi":"10.1016/j.molcel.2024.10.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.020","url":null,"abstract":"The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription. Second, ARF targets the RUNX family transcription factor 1 (RUNX1) to selectively tune gene transcription. Consistently, ARF loss triggers RUNX1- and PAF1c-dependent transcriptional activation of pro-growth ligands (growth differentiation factor/bone morphogenetic protein [GDF/BMP]), promoting a cell-intrinsic GDF/BMP-Smad1/5 axis that aberrantly induce cell growth. Notably, pharmacologic inactivation of GDF/BMP signaling and genetic perturbation of RUNX1 significantly attenuate cell proliferation mediated by dual p53 and ARF loss, offering therapeutic utility. Our data underscore the significance of selective ARF-mediated tumor-suppressive functions through a universal transcriptional regulator.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"10 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599538","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 : 2024-11-11DOI: 10.1016/j.molcel.2024.10.025
Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G. Ganley
Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.
{"title":"Opposing roles for AMPK in regulating distinct mitophagy pathways","authors":"Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G. Ganley","doi":"10.1016/j.molcel.2024.10.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.025","url":null,"abstract":"Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues <em>in vivo</em>, using the <em>mito</em>-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"71 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599539","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 : 2024-11-08DOI: 10.1016/j.molcel.2024.10.022
Lipophagy is a ubiquitous mechanism for degradation of lipid droplets (LDs) in lysosomes. Autophagy receptors selectively target organelles for lysoso…
自噬是溶酶体中降解脂滴（LD）的一种普遍机制。自噬受体可选择性地将细胞器作为溶酶体的目标...
{"title":"VPS4A is the selective receptor for lipophagy in mice and humans","authors":"","doi":"10.1016/j.molcel.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.022","url":null,"abstract":"Lipophagy is a ubiquitous mechanism for degradation of lipid droplets (LDs) in lysosomes. Autophagy receptors selectively target organelles for lysoso…","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"9 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596849","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 : 2024-11-07DOI: 10.1016/j.molcel.2024.10.019
Khadija Shahed Khan, Billy Wai-Lung Ng
In this issue, Won et al.1 report a covalent ligand binding the pioneer transcription factor FOXA1, altering its function and remodeling chromatin. This important finding highlights the potential of small molecules to modulate transcription factor activity and demonstrates the promise of chemical proteomics in discovering first-in-class ligands.
{"title":"A small molecule that reshapes the chromatin dynamics of FOXA1","authors":"Khadija Shahed Khan, Billy Wai-Lung Ng","doi":"10.1016/j.molcel.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.019","url":null,"abstract":"In this issue, Won et al.<span><span><sup>1</sup></span></span> report a covalent ligand binding the pioneer transcription factor FOXA1, altering its function and remodeling chromatin. This important finding highlights the potential of small molecules to modulate transcription factor activity and demonstrates the promise of chemical proteomics in discovering first-in-class ligands.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594590","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 : 2024-11-07DOI: 10.1016/j.molcel.2024.10.013
Zhifu Han, Yu Cao, Jijie Chai
In this issue of Molecular Cell, Luo et al.1 identify a signaling pathway, OSM1-COLD6, that induces cold tolerance in rice by promoting production of the non-canonical cyclic nucleotide 2′,3′-cAMP. The study opens new avenues for enhancing cold tolerance in rice breeding.
{"title":"Inducing rice chilling tolerance by the second messenger 2′,3′-cAMP","authors":"Zhifu Han, Yu Cao, Jijie Chai","doi":"10.1016/j.molcel.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.013","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Luo et al.<span><span><sup>1</sup></span></span> identify a signaling pathway, OSM1-COLD6, that induces cold tolerance in rice by promoting production of the non-canonical cyclic nucleotide 2′,3′-cAMP. The study opens new avenues for enhancing cold tolerance in rice breeding.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"15 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594588","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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