دورية أكاديمية
Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence.
العنوان: | Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence. |
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المؤلفون: | Haarer EL; Department of Molecular and Cell Biology; University of Connecticut, Storrs, Connecticut, United States of America.; Institute for Systems Genomics; University of Connecticut, Storrs, Connecticut, United States of America., Theodore CJ; Department of Molecular and Cell Biology; University of Connecticut, Storrs, Connecticut, United States of America.; Institute for Systems Genomics; University of Connecticut, Storrs, Connecticut, United States of America., Guo S; Department of Molecular and Cell Biology; University of Connecticut, Storrs, Connecticut, United States of America.; Institute for Systems Genomics; University of Connecticut, Storrs, Connecticut, United States of America., Frier RB; Department of Molecular and Cell Biology; University of Connecticut, Storrs, Connecticut, United States of America.; Institute for Systems Genomics; University of Connecticut, Storrs, Connecticut, United States of America., Campellone KG; Department of Molecular and Cell Biology; University of Connecticut, Storrs, Connecticut, United States of America.; Institute for Systems Genomics; University of Connecticut, Storrs, Connecticut, United States of America.; Center on Aging, UConn Health; University of Connecticut, Storrs, Connecticut, United States of America. |
المصدر: | PLoS genetics [PLoS Genet] 2023 Jan 27; Vol. 19 (1), pp. e1010045. Date of Electronic Publication: 2023 Jan 27 (Print Publication: 2023). |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: San Francisco, CA : Public Library of Science, c2005- |
مواضيع طبية MeSH: | Actin-Related Protein 2-3 Complex*/genetics , Actin-Related Protein 2-3 Complex*/metabolism , Actins*/metabolism, Animals ; Mice ; Cellular Senescence/genetics ; DNA/metabolism ; Genomic Instability/genetics ; Mitosis/genetics |
مستخلص: | The Arp2/3 complex is an actin nucleator with well-characterized activities in cell morphogenesis and movement, but its roles in nuclear processes are relatively understudied. We investigated how the Arp2/3 complex affects genomic integrity and cell cycle progression using mouse fibroblasts containing an inducible knockout (iKO) of the ArpC2 subunit. We show that permanent Arp2/3 complex ablation results in DNA damage, the formation of cytosolic micronuclei, and cellular senescence. Micronuclei arise in ArpC2 iKO cells due to chromatin segregation defects during mitosis and premature mitotic exits. Such phenotypes are explained by the presence of damaged DNA fragments that fail to attach to the mitotic spindle, abnormalities in actin assembly during metaphase, and asymmetric microtubule architecture during anaphase. In the nuclei of Arp2/3-depleted cells, the tumor suppressor p53 is activated and the cell cycle inhibitor Cdkn1a/p21 mediates a G1 arrest. In the cytosol, micronuclei are recognized by the DNA sensor cGAS, which is important for stimulating a STING- and IRF3-associated interferon response. These studies establish functional requirements for the mammalian Arp2/3 complex in mitotic spindle organization and genome stability. They also expand our understanding of the mechanisms leading to senescence and suggest that cytoskeletal dysfunction is an underlying factor in biological aging. Competing Interests: The authors have declared that no competing interests exist. (Copyright: © 2023 Haarer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.) |
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معلومات مُعتمدة: | K02 AG050774 United States AG NIA NIH HHS; R01 GM107441 United States GM NIGMS NIH HHS |
المشرفين على المادة: | 0 (Actin-Related Protein 2-3 Complex) 0 (Actins) 9007-49-2 (DNA) |
تواريخ الأحداث: | Date Created: 20230127 Date Completed: 20230213 Latest Revision: 20230215 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC9907832 |
DOI: | 10.1371/journal.pgen.1010045 |
PMID: | 36706133 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1553-7404 |
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DOI: | 10.1371/journal.pgen.1010045 |