دورية أكاديمية
أعرض في EDS

Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence.

التفاصيل البيبلوغرافية
العنوان: Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence.
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.)
References: Nat Rev Mol Cell Biol. 2013 Jan;14(1):7-12. (PMID: 23212475)
Nat Commun. 2017 Sep 29;8(1):750. (PMID: 28963528)
Elife. 2019 Dec 06;8:. (PMID: 31808743)
Curr Biol. 2021 May 24;31(10):R603-R618. (PMID: 34033793)
Cancers (Basel). 2020 Mar 29;12(4):. (PMID: 32235364)
Front Immunol. 2021 May 03;12:646304. (PMID: 34012437)
Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):E3820-9. (PMID: 24043783)
Nat Aging. 2021 Oct;1(10):962-973. (PMID: 35024619)
J Cell Sci. 2003 Apr 15;116(Pt 8):1505-18. (PMID: 12640035)
Mol Biol Cell. 2015 Jun 1;26(11):1995-2004. (PMID: 25833710)
Annu Rev Pathol. 2010;5:99-118. (PMID: 20078217)
Mol Biol Cell. 2018 Oct 15;29(21):2522-2527. (PMID: 30133343)
Cell. 2012 Mar 2;148(5):973-87. (PMID: 22385962)
Cell. 2019 Oct 31;179(4):813-827. (PMID: 31675495)
Cell. 2008 Jul 11;134(1):148-61. (PMID: 18614018)
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6181-6. (PMID: 9600938)
BMC Genet. 2007 Jun 06;8:28. (PMID: 17553170)
Nat Commun. 2016 Jun 21;7:11932. (PMID: 27324217)
PLoS One. 2011;6(11):e27233. (PMID: 22073297)
J Cell Biol. 1997 Jul 28;138(2):375-84. (PMID: 9230079)
PLoS Genet. 2021 Apr 19;17(4):e1009512. (PMID: 33872315)
Nature. 2011 Nov 02;479(7372):232-6. (PMID: 22048312)
Development. 2020 Nov 15;147(22):. (PMID: 33028610)
Trends Cell Biol. 2018 Jun;28(6):436-453. (PMID: 29477613)
Curr Opin Physiol. 2018 Jun;3:94-100. (PMID: 30555978)
Nature. 2018 Jul;559(7712):54-60. (PMID: 29925946)
Curr Opin Cell Biol. 2016 Oct;42:63-72. (PMID: 27164504)
Mol Cell Biol. 2006 Aug;26(16):6185-96. (PMID: 16880528)
EMBO J. 2019 Jun 3;38(11):. (PMID: 30902847)
Exp Mol Med. 2020 Apr;52(4):643-657. (PMID: 32284536)
Mol Cancer Res. 2003 Feb;1(4):262-70. (PMID: 12612054)
J Cell Biol. 2021 Aug 2;220(8):. (PMID: 34096975)
Nature. 2005 Aug 11;436(7052):812-8. (PMID: 16015286)
J Exp Med. 2018 May 7;215(5):1287-1299. (PMID: 29622565)
J Cell Biol. 2018 Aug 6;217(8):2661-2674. (PMID: 29903878)
F1000Res. 2017 Dec 11;6:2121. (PMID: 29263785)
Nature. 2009 Aug 20;460(7258):1031-4. (PMID: 19648907)
Science. 2015 Mar 13;347(6227):aaa2630. (PMID: 25636800)
Nat Rev Mol Cell Biol. 2019 Apr;20(4):199-210. (PMID: 30824861)
Cell Res. 2019 Jun;29(6):432-445. (PMID: 30971746)
PLoS Biol. 2020 Jan 16;18(1):e3000599. (PMID: 31945054)
Nat Rev Mol Cell Biol. 2020 Sep;21(9):501-521. (PMID: 32424334)
Nucleus. 2020 Dec;11(1):35-52. (PMID: 32208955)
Science. 2017 Aug 25;357(6353):. (PMID: 28839045)
Nature. 2017 Aug 24;548(7668):461-465. (PMID: 28738408)
FEBS Lett. 2007 Dec 11;581(29):5691-7. (PMID: 18035060)
Curr Biol. 2008 Oct 14;18(19):1514-9. (PMID: 18848445)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
PLoS Biol. 2008 Dec 2;6(12):2853-68. (PMID: 19053174)
Exp Cell Res. 1965 Mar;37:614-36. (PMID: 14315085)
Mol Cell. 2001 Nov;8(5):1041-52. (PMID: 11741539)
Science. 2014 Oct 17;346(6207):360-3. (PMID: 25324391)
Aging Cell. 2006 Apr;5(2):187-95. (PMID: 16626397)
Elife. 2015 Aug 19;4:e07735. (PMID: 26287480)
Nat Rev Immunol. 2023 Feb;23(2):75-89. (PMID: 35831609)
J Cell Biol. 2013 Dec 23;203(6):907-16. (PMID: 24344184)
Cell. 2017 Sep 7;170(6):1062-1078. (PMID: 28886379)
Dev Cell. 2015 Jan 12;32(1):54-67. (PMID: 25543281)
Curr Biol. 1998 Dec 17-31;8(25):1347-56. (PMID: 9889097)
Nature. 1992 Jan 9;355(6356):179-82. (PMID: 1729653)
Nature. 2019 May;569(7758):718-722. (PMID: 31118511)
Cell. 2008 Jun 13;133(6):1019-31. (PMID: 18555778)
Cancer Res. 2006 Sep 1;66(17):8356-60. (PMID: 16951143)
Nature. 2018 Jul;559(7712):61-66. (PMID: 29925947)
Dev Cell. 2004 Nov;7(5):637-51. (PMID: 15525526)
Cold Spring Harb Perspect Biol. 2016 Aug 01;8(8):. (PMID: 26988969)
Cell. 2007 Jul 27;130(2):223-33. (PMID: 17662938)
Mol Biol Cell. 2006 Jun;17(6):2581-91. (PMID: 16597702)
Nat Cell Biol. 2017 Sep;19(9):1061-1070. (PMID: 28759028)
Cancer Res. 2016 Sep 15;76(18):5189-91. (PMID: 27635040)
EMBO J. 2019 Jun 3;38(11):. (PMID: 31015335)
Nat Aging. 2021 Oct;1(10):870-879. (PMID: 34841261)
Nat Immunol. 2016 Sep 20;17(10):1142-9. (PMID: 27648547)
Curr Biol. 2002 Apr 30;12(9):705-11. (PMID: 12007413)
J Cell Biol. 2002 Feb 18;156(4):677-87. (PMID: 11854308)
J Cell Sci. 2000 Oct;113 ( Pt 20):3613-22. (PMID: 11017877)
Front Cell Dev Biol. 2021 Mar 29;9:645593. (PMID: 33855023)
Mol Biol Cell. 2019 Jul 1;30(14):1645-1654. (PMID: 31091161)
Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363-7. (PMID: 7568133)
Mol Biol Cell. 2012 Jun;23(11):2066-75. (PMID: 22496421)
Nat Cell Biol. 2016 Jan;18(1):65-75. (PMID: 26655833)
EMBO J. 2003 Aug 15;22(16):4212-22. (PMID: 12912919)
Elife. 2021 Jan 29;10:. (PMID: 33512316)
Dev Biol. 2008 Dec 15;324(2):297-309. (PMID: 18938151)
Nat Commun. 2020 Jul 7;11(1):3382. (PMID: 32636381)
PLoS Biol. 2019 Oct 10;17(10):e3000457. (PMID: 31600188)
Sci Signal. 2012 Mar 06;5(214):ra20. (PMID: 22394562)
Mutagenesis. 2011 Jan;26(1):125-32. (PMID: 21164193)
J Cell Biol. 2012 Apr 16;197(2):239-51. (PMID: 22492726)
PLoS One. 2015 Apr 02;10(4):e0123438. (PMID: 25837661)
Nature. 2012 Jan 18;482(7383):53-8. (PMID: 22258507)
Oncogene. 2011 May 19;30(20):2356-66. (PMID: 21242976)
J Cell Biol. 2013 Jul 8;202(1):129-43. (PMID: 23816621)
J Neurosci. 2013 Apr 3;33(14):6081-92. (PMID: 23554489)
BMB Rep. 2016 Nov;49(11):598-606. (PMID: 27470213)
Chem Biol. 2013 May 23;20(5):701-12. (PMID: 23623350)
Front Cell Dev Biol. 2021 Feb 01;9:634708. (PMID: 33598464)
Nature. 2019 Mar;567(7748):394-398. (PMID: 30842653)
Nat Rev Mol Cell Biol. 2010 Apr;11(4):237-51. (PMID: 20237478)
Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7288-93. (PMID: 10377407)
Nat Rev Mol Cell Biol. 2021 Feb;22(2):75-95. (PMID: 33328614)
Exp Cell Res. 1961 Dec;25:585-621. (PMID: 13905658)
Nature. 2016 Feb 11;530(7589):184-9. (PMID: 26840489)
J Biol Chem. 1998 Mar 6;273(10):5858-68. (PMID: 9488723)
EMBO J. 2021 Aug 16;40(16):e108293. (PMID: 34250619)
Nat Cell Biol. 2016 Jan;18(1):76-86. (PMID: 26655834)
Development. 2016 Aug 1;143(15):2741-52. (PMID: 27385014)
iScience. 2019 May 31;15:274-281. (PMID: 31096079)
Nature. 2017 Oct 19;550(7676):402-406. (PMID: 28976970)
Nat Rev Cancer. 2009 Jun;9(6):400-14. (PMID: 19440234)
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
الوصف
تدمد:1553-7404
DOI:10.1371/journal.pgen.1010045