Pub Date : 2025-02-06DOI: 10.1016/j.molcel.2025.01.016
Chase C. Suiter, Diego Calderon, David S. Lee, Melodie Chiu, Shruti Jain, Florence M. Chardon, Choli Lee, Riza M. Daza, Cole Trapnell, Ning Zheng, Jay Shendure
E3 ubiquitin ligases (E3s) confer specificity of protein degradation through ubiquitination of substrate proteins. Yet, the vast majority of the >600 human E3s have no known substrates. To identify proteolytic E3-substrate pairs at scale, we developed combinatorial mapping of E3 targets (COMET), a framework for testing the role of many E3s in degrading many candidate substrates within a single experiment. We applied COMET to SCF ubiquitin ligase subunits that mediate degradation of target substrates (6,716 F-box-ORF [open reading frame] combinations) and E3s that degrade short-lived transcription factors (TFs) (26,028 E3-TF combinations). Our data suggest that many E3-substrate relationships are complex rather than 1:1 associations. Finally, we leverage deep learning to predict the structural basis of E3-substrate interactions and probe the strengths and limits of such models. Looking forward, we consider the practicality of transposing this framework, i.e., computational structural prediction of all possible E3-substrate interactions, followed by multiplex experimental validation.
{"title":"Combinatorial mapping of E3 ubiquitin ligases to their target substrates","authors":"Chase C. Suiter, Diego Calderon, David S. Lee, Melodie Chiu, Shruti Jain, Florence M. Chardon, Choli Lee, Riza M. Daza, Cole Trapnell, Ning Zheng, Jay Shendure","doi":"10.1016/j.molcel.2025.01.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.016","url":null,"abstract":"E3 ubiquitin ligases (E3s) confer specificity of protein degradation through ubiquitination of substrate proteins. Yet, the vast majority of the >600 human E3s have no known substrates. To identify proteolytic E3-substrate pairs at scale, we developed combinatorial mapping of E3 targets (COMET), a framework for testing the role of many E3s in degrading many candidate substrates within a single experiment. We applied COMET to SCF ubiquitin ligase subunits that mediate degradation of target substrates (6,716 F-box-ORF [open reading frame] combinations) and E3s that degrade short-lived transcription factors (TFs) (26,028 E3-TF combinations). Our data suggest that many E3-substrate relationships are complex rather than 1:1 associations. Finally, we leverage deep learning to predict the structural basis of E3-substrate interactions and probe the strengths and limits of such models. Looking forward, we consider the practicality of transposing this framework, i.e., computational structural prediction of all possible E3-substrate interactions, followed by multiplex experimental validation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"15 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192626","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 : 2025-02-06DOI: 10.1016/j.molcel.2025.01.009
Vita Zhang, Amy S. Gladfelter, Christine A. Roden
In this issue of Molecular Cell, Trussina et al. and Parker et al. present complementary lines of evidence that suggest that stress granules regulate trans RNA-RNA interactions through the action of helicase proteins, which destabilize persistent RNA-RNA interactions that are sufficient to maintain condensate integrity.1,2
{"title":"Biomolecular condensates: It was RNA all along!","authors":"Vita Zhang, Amy S. Gladfelter, Christine A. Roden","doi":"10.1016/j.molcel.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.009","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Trussina et al. and Parker et al. present complementary lines of evidence that suggest that stress granules regulate <em>trans</em> RNA-RNA interactions through the action of helicase proteins, which destabilize persistent RNA-RNA interactions that are sufficient to maintain condensate integrity.<span><span><sup>1</sup></span></span><sup>,</sup><span><span><sup>2</sup></span></span>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"40 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192627","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 : 2025-02-06DOI: 10.1016/j.molcel.2025.01.007
Martine A. Collart, Olesya O. Panasenko
The study by Mallik et al.1 tackles the question of protein assembly in living cells, particularly how extensively co-translational assembly occurs and what rules govern the process. It reveals overarching impact of three-dimensional protein structure for defining assembly pathway.
{"title":"Assembly in action: Protein structure orchestrates assembly pathway, and intertwining defines co-translational assembly","authors":"Martine A. Collart, Olesya O. Panasenko","doi":"10.1016/j.molcel.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.007","url":null,"abstract":"The study by Mallik et al.<span><span><sup>1</sup></span></span> tackles the question of protein assembly in living cells, particularly how extensively co-translational assembly occurs and what rules govern the process. It reveals overarching impact of three-dimensional protein structure for defining assembly pathway.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"16 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192628","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 : 2025-02-06DOI: 10.1016/j.molcel.2025.01.015
Emmanuelle Genoyer, Jonathan Wilson, Joshua M. Ames, Caleb Stokes, Dante Moreno, Noa Etzyon, Andrew Oberst, Michael Gale
For many RNA viruses, immunity is triggered when RIG-I-like receptors (RLRs) detect viral RNA. However, only a minority of infected cells undergo innate immune activation. By examining these “first-responder” cells during West Nile virus infection, we found that specific accumulation of antigenomic negative-sense viral RNA (−vRNA) underlies innate immune activation and that RIG-I preferentially interacts with −vRNA. However, flaviviruses sequester −vRNA into membrane-bound replication compartments away from cytosolic sensors. We found that single-stranded −vRNA accumulates outside of replication compartments in first-responder cells, rendering it accessible to RLRs. Exposure of this −vRNA occurs at late time points of infection, is linked to viral assembly, and depends on the expression of viral structural proteins. These findings reveal that, although most infected cells replicate high levels of vRNA, release of −vRNA from replication compartments during assembly occurs at low frequency and is critical for initiation of innate immunity during flavivirus infection.
{"title":"Exposure of negative-sense viral RNA in the cytoplasm initiates innate immunity to West Nile virus","authors":"Emmanuelle Genoyer, Jonathan Wilson, Joshua M. Ames, Caleb Stokes, Dante Moreno, Noa Etzyon, Andrew Oberst, Michael Gale","doi":"10.1016/j.molcel.2025.01.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.015","url":null,"abstract":"For many RNA viruses, immunity is triggered when RIG-I-like receptors (RLRs) detect viral RNA. However, only a minority of infected cells undergo innate immune activation. By examining these “first-responder” cells during West Nile virus infection, we found that specific accumulation of antigenomic negative-sense viral RNA (−vRNA) underlies innate immune activation and that RIG-I preferentially interacts with −vRNA. However, flaviviruses sequester −vRNA into membrane-bound replication compartments away from cytosolic sensors. We found that single-stranded −vRNA accumulates outside of replication compartments in first-responder cells, rendering it accessible to RLRs. Exposure of this −vRNA occurs at late time points of infection, is linked to viral assembly, and depends on the expression of viral structural proteins. These findings reveal that, although most infected cells replicate high levels of vRNA, release of −vRNA from replication compartments during assembly occurs at low frequency and is critical for initiation of innate immunity during flavivirus infection.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"46 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192529","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 : 2025-02-06DOI: 10.1016/j.molcel.2025.01.005
Alma Sophia Barisaac, Enas R. Abu-Zhayia, Nabieh Ayoub
Metabolite microenvironment shapes cancer treatment strategies. In a recent paper in Nature, Jin et al.1 demonstrate that valine deprivation triggers HDAC6 entry into the nucleus, leading to accumulation of DNA damage that could be harnessed for targeted cancer therapy.
代谢物微环境塑造了癌症治疗策略。在最近发表于《自然》（Nature）的一篇论文中，Jin 等人1 证明，缬氨酸缺乏会触发 HDAC6 进入细胞核，导致 DNA 损伤积累，从而可用于癌症靶向治疗。
{"title":"Leveraging valine-restriction-induced DNA damage for targeted cancer therapy","authors":"Alma Sophia Barisaac, Enas R. Abu-Zhayia, Nabieh Ayoub","doi":"10.1016/j.molcel.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.005","url":null,"abstract":"Metabolite microenvironment shapes cancer treatment strategies. In a recent paper in <em>Nature</em>, Jin et al.<span><span><sup>1</sup></span></span> demonstrate that valine deprivation triggers HDAC6 entry into the nucleus, leading to accumulation of DNA damage that could be harnessed for targeted cancer therapy.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"9 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192629","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}
Impairment of ribosome biogenesis (RiBi) triggered by inhibition of ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility in the ribosomal DNA (rDNA) genes. SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis in response to replication stress. SLFN11’s Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for single-strand DNA binding (S753), and RNase sites (E209/E214) are all required for the SLFN11-mediated RiBi impairment. Comparable effects were obtained with direct RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were extended across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an additional proapoptotic mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.
{"title":"SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis","authors":"Akane Ogawa, Keiichi Izumikawa, Sota Tate, Sho Isoyama, Masaru Mori, Kohei Fujiwara, Soyoka Watanabe, Takayuki Ohga, Ukhyun Jo, Daiki Taniyama, Shojiro Kitajima, Soichiro Tanaka, Hiroshi Onji, Shun-Ichiro Kageyama, Gaku Yamamoto, Hitoshi Saito, Tomoko Yamamori Morita, Masayasu Okada, Manabu Natsumeda, Masami Nagahama, Junko Murai","doi":"10.1016/j.molcel.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.008","url":null,"abstract":"Impairment of ribosome biogenesis (RiBi) triggered by inhibition of ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility in the ribosomal DNA (rDNA) genes. SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis in response to replication stress. SLFN11’s Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for single-strand DNA binding (S753), and RNase sites (E209/E214) are all required for the SLFN11-mediated RiBi impairment. Comparable effects were obtained with direct RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were extended across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an additional proapoptotic mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"38 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083536","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 : 2025-02-04DOI: 10.1016/j.molcel.2025.01.029
Sujin Kim, Stephanie Tan, Jayoung Ku, Tria Asri Widowati, Doyeong Ku, Keonyong Lee, Kwontae You, Yoosik Kim
(Molecular Cell 84, 2935–2948.e1–e7; August 8, 2024)
{"title":"RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release","authors":"Sujin Kim, Stephanie Tan, Jayoung Ku, Tria Asri Widowati, Doyeong Ku, Keonyong Lee, Kwontae You, Yoosik Kim","doi":"10.1016/j.molcel.2025.01.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.029","url":null,"abstract":"(Molecular Cell <em>84</em>, 2935–2948.e1–e7; August 8, 2024)","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"40 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124995","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 : 2025-02-04DOI: 10.1016/j.molcel.2025.01.010
Adrian Bird
Cohesin is a multi-subunit molecular machine that is able to create lateral chromatin loops within a linear chromosome fiber. Despite intense study, a consensus view of the functional significance of loop extrusion has remained elusive. This perspective proposes a rationale based on the need for continual disruption of spurious higher-order chromatin secondary structures. It is argued that cohesin-mediated chromosomal churn ensures broad accessibility to the diffusible factors on which genome function depends.
{"title":"Cohesin as an essential disruptor of chromosome organization","authors":"Adrian Bird","doi":"10.1016/j.molcel.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.010","url":null,"abstract":"Cohesin is a multi-subunit molecular machine that is able to create lateral chromatin loops within a linear chromosome fiber. Despite intense study, a consensus view of the functional significance of loop extrusion has remained elusive. This perspective proposes a rationale based on the need for continual disruption of spurious higher-order chromatin secondary structures. It is argued that cohesin-mediated chromosomal churn ensures broad accessibility to the diffusible factors on which genome function depends.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"13 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083537","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 : 2025-01-31DOI: 10.1016/j.molcel.2025.01.003
Raja H. Ali, Esteban A. Orellana, Su Hyun Lee, Yun-Cheol Chae, Yantao Chen, Jim Clauwaert, Alyssa L. Kennedy, Ashley E. Gutierrez, David J. Papke, Mateo Valenzuela, Brianna Silverman, Amanda Falzetta, Scott B. Ficarro, Jarrod A. Marto, Christopher D.M. Fletcher, Antonio Perez-Atayde, Thierry Alcindor, Akiko Shimamura, John R. Prensner, Richard I. Gregory, Alejandro Gutierrez
Amplification of chromosomal material derived from 12q13-15 is common in human cancer and believed to result in overexpression of multiple collaborating oncogenes. To define the oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase METTL1. This was surprising, because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases and promotes tRNA aminoacylation, polysome formation, and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. We propose that METTL1 overexpression promotes sarcomagenesis by stimulating tRNA aminoacylation, protein synthesis, and tumor cell growth independent of its methyltransferase activity.
{"title":"A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation","authors":"Raja H. Ali, Esteban A. Orellana, Su Hyun Lee, Yun-Cheol Chae, Yantao Chen, Jim Clauwaert, Alyssa L. Kennedy, Ashley E. Gutierrez, David J. Papke, Mateo Valenzuela, Brianna Silverman, Amanda Falzetta, Scott B. Ficarro, Jarrod A. Marto, Christopher D.M. Fletcher, Antonio Perez-Atayde, Thierry Alcindor, Akiko Shimamura, John R. Prensner, Richard I. Gregory, Alejandro Gutierrez","doi":"10.1016/j.molcel.2025.01.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.003","url":null,"abstract":"Amplification of chromosomal material derived from 12q13-15 is common in human cancer and believed to result in overexpression of multiple collaborating oncogenes. To define the oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase <em>METTL1</em>. This was surprising, because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases and promotes tRNA aminoacylation, polysome formation, and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. We propose that METTL1 overexpression promotes sarcomagenesis by stimulating tRNA aminoacylation, protein synthesis, and tumor cell growth independent of its methyltransferase activity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071937","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 : 2025-01-30DOI: 10.1016/j.molcel.2025.01.004
Emily S. Smith-Pillet, Ramya Billur, Marie-France Langelier, Tanaji T. Talele, John M. Pascal, Ben E. Black
Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current FDA-approved forms of PARP inhibitors (PARPi) used in the cancer clinic. Recent evidence indicates that the same PARPi molecules impact PARP2 differently from PARP1, raising the possibility that allosteric activation may also differ. We find that, unlike for PARP1, destabilization of the autoinhibitory domain of PARP2 is insufficient for DNA damage-induced catalytic activation. Rather, PARP2 activation requires further unfolding of an active site helix. In contrast, the corresponding helix in PARP1 only transiently forms, even prior to engaging DNA. Only one clinical PARPi, Olaparib, stabilizes the PARP2 active site helix, representing a structural feature with the potential to discriminate small molecule inhibitors. Collectively, our findings reveal unanticipated differences in local structure and changes in activation-coupled backbone dynamics between human PARP1 and PARP2.
{"title":"A PARP2 active site helix melts to permit DNA damage-induced enzymatic activation","authors":"Emily S. Smith-Pillet, Ramya Billur, Marie-France Langelier, Tanaji T. Talele, John M. Pascal, Ben E. Black","doi":"10.1016/j.molcel.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.004","url":null,"abstract":"Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current FDA-approved forms of PARP inhibitors (PARPi) used in the cancer clinic. Recent evidence indicates that the same PARPi molecules impact PARP2 differently from PARP1, raising the possibility that allosteric activation may also differ. We find that, unlike for PARP1, destabilization of the autoinhibitory domain of PARP2 is insufficient for DNA damage-induced catalytic activation. Rather, PARP2 activation requires further unfolding of an active site helix. In contrast, the corresponding helix in PARP1 only transiently forms, even prior to engaging DNA. Only one clinical PARPi, Olaparib, stabilizes the PARP2 active site helix, representing a structural feature with the potential to discriminate small molecule inhibitors. Collectively, our findings reveal unanticipated differences in local structure and changes in activation-coupled backbone dynamics between human PARP1 and PARP2.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"36 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056423","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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