Pub Date : 2026-01-09DOI: 10.1038/s41556-025-01852-1
Tyler H Stanage,Shudong Li,Sandra Segura-Bayona,Aurora I Idilli,Rhona Millar,Graeme Hewitt,Simon J Boulton
SLFN11 is epigenetically silenced and confers chemoresistance in half of all cancers. In response to replication stress, SLFN11 triggers translation shutdown and p53-independent apoptosis, but how DNA damage activates SLFN11 remains unclear. Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase-polymerase (PrimPol)-mediated repriming. SLFN11 and the downstream integrated stress response uniquely promote cisplatin-driven apoptosis in PrimPol-deficient cells. We demonstrate that replication protein A (RPA) exhaustion and single-stranded DNA exposure trigger SLFN11 activation and cell death when PrimPol is inactivated. We further identify the USP1-WDR48 deubiquitinase complex as a positive modulator of SLFN11 activation in PrimPol-deficient cells, revealing an addiction to the Fanconi anaemia pathway to resolve cisplatin lesions. Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress.
{"title":"RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress.","authors":"Tyler H Stanage,Shudong Li,Sandra Segura-Bayona,Aurora I Idilli,Rhona Millar,Graeme Hewitt,Simon J Boulton","doi":"10.1038/s41556-025-01852-1","DOIUrl":"https://doi.org/10.1038/s41556-025-01852-1","url":null,"abstract":"SLFN11 is epigenetically silenced and confers chemoresistance in half of all cancers. In response to replication stress, SLFN11 triggers translation shutdown and p53-independent apoptosis, but how DNA damage activates SLFN11 remains unclear. Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase-polymerase (PrimPol)-mediated repriming. SLFN11 and the downstream integrated stress response uniquely promote cisplatin-driven apoptosis in PrimPol-deficient cells. We demonstrate that replication protein A (RPA) exhaustion and single-stranded DNA exposure trigger SLFN11 activation and cell death when PrimPol is inactivated. We further identify the USP1-WDR48 deubiquitinase complex as a positive modulator of SLFN11 activation in PrimPol-deficient cells, revealing an addiction to the Fanconi anaemia pathway to resolve cisplatin lesions. Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"244 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937789","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 : 2026-01-07DOI: 10.1038/s41556-025-01844-1
Ruben van der Lugt, Jacqueline J. L. Jacobs
{"title":"Structural organization and function of telomeric chromatin","authors":"Ruben van der Lugt, Jacqueline J. L. Jacobs","doi":"10.1038/s41556-025-01844-1","DOIUrl":"https://doi.org/10.1038/s41556-025-01844-1","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"102 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907947","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 : 2026-01-07DOI: 10.1038/s41556-025-01853-0
Jossie J. Yashinskie, Xianbing Zhu, Grace H. McGregor, Karl A. Wessendorf-Rodriguez, Katrina Paras, Julia S. Brunner, Benjamin T. Jackson, Abigail Xie, Richard Koche, Christian M. Metallo, Lydia W. S. Finley
{"title":"p53 increases phospholipid headgroup scavenging in senescence","authors":"Jossie J. Yashinskie, Xianbing Zhu, Grace H. McGregor, Karl A. Wessendorf-Rodriguez, Katrina Paras, Julia S. Brunner, Benjamin T. Jackson, Abigail Xie, Richard Koche, Christian M. Metallo, Lydia W. S. Finley","doi":"10.1038/s41556-025-01853-0","DOIUrl":"https://doi.org/10.1038/s41556-025-01853-0","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"167 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907951","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 : 2026-01-06DOI: 10.1038/s41556-025-01785-9
Dario Rizzotto, Christian Zierhut, Andreas Villunger
Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular processes are uniquely regulated. Ultimately, cells arrested during mitosis may die, but adaptive mechanisms also allow their escape into the next interphase. This step can have variable consequences, including chromosome missegregation, polyploidization and centrosome amplification. Escaping cells can also initiate innate immune signalling, enter senescence or engage cell death, which in turn alert the microenvironment through nucleic acid sensing mechanisms and/or the release of danger-associated molecular patterns. Here we discuss the causes and consequences of deregulated mitosis and postmitotic cell fate, highlighting the impact of DNA damage repair, the spindle assembly checkpoint and extra centrosomes on genome integrity, as well as inflammatory signalling. Finally, we attempt to reconcile conflicting observations and propose variable modes that activate innate immune responses after mitotic perturbations. Rizzotto et al. discuss the causes and consequences of deregulated mitosis that allow cells arrested in mitosis to escape to the next interphase, where they can initiate inflammatory signalling or undergo cell death, with therapeutic implications.
{"title":"Mitotic errors as triggers of cell death and inflammation","authors":"Dario Rizzotto, Christian Zierhut, Andreas Villunger","doi":"10.1038/s41556-025-01785-9","DOIUrl":"10.1038/s41556-025-01785-9","url":null,"abstract":"Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular processes are uniquely regulated. Ultimately, cells arrested during mitosis may die, but adaptive mechanisms also allow their escape into the next interphase. This step can have variable consequences, including chromosome missegregation, polyploidization and centrosome amplification. Escaping cells can also initiate innate immune signalling, enter senescence or engage cell death, which in turn alert the microenvironment through nucleic acid sensing mechanisms and/or the release of danger-associated molecular patterns. Here we discuss the causes and consequences of deregulated mitosis and postmitotic cell fate, highlighting the impact of DNA damage repair, the spindle assembly checkpoint and extra centrosomes on genome integrity, as well as inflammatory signalling. Finally, we attempt to reconcile conflicting observations and propose variable modes that activate innate immune responses after mitotic perturbations. Rizzotto et al. discuss the causes and consequences of deregulated mitosis that allow cells arrested in mitosis to escape to the next interphase, where they can initiate inflammatory signalling or undergo cell death, with therapeutic implications.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"21-34"},"PeriodicalIF":19.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902710","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 : 2026-01-06DOI: 10.1038/s41556-025-01784-w
Colin Richard Gliech, Andrew Jon Holland
Accurate chromosome segregation is vital for organismal development and homeostasis, with errors in this process strongly associated with tumourigenesis. A network of safeguard clocks preserves mitotic fidelity by detecting and eliminating cells dividing outside the stereotyped duration of successful mitosis. This Perspective examines recent advances in our understanding of mitotic timing mechanisms, presents emerging evidence for novel mitotic clocks and proposes a conceptual framework for how cells integrate temporal cues to preserve genomic integrity. This Perspective discusses our current understanding of the timing mechanisms that couple mitotic duration to cell fate, including emerging evidence for the existence of mitotic clocks that enable cells to preserve genomic integrity.
{"title":"Biological clocks keep a watch on mitosis","authors":"Colin Richard Gliech, Andrew Jon Holland","doi":"10.1038/s41556-025-01784-w","DOIUrl":"10.1038/s41556-025-01784-w","url":null,"abstract":"Accurate chromosome segregation is vital for organismal development and homeostasis, with errors in this process strongly associated with tumourigenesis. A network of safeguard clocks preserves mitotic fidelity by detecting and eliminating cells dividing outside the stereotyped duration of successful mitosis. This Perspective examines recent advances in our understanding of mitotic timing mechanisms, presents emerging evidence for novel mitotic clocks and proposes a conceptual framework for how cells integrate temporal cues to preserve genomic integrity. This Perspective discusses our current understanding of the timing mechanisms that couple mitotic duration to cell fate, including emerging evidence for the existence of mitotic clocks that enable cells to preserve genomic integrity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"13-20"},"PeriodicalIF":19.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902709","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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