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Showing content from https://pubmed.ncbi.nlm.nih.gov/31366473/ below:

Nuclear failure, DNA damage, and cell cycle disruption after migration through small pores: a brief review

Review

Affiliations

• ¹ Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA.

• PMID: 31366473
• DOI: 10.1042/EBC20190007

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Review

Charlotte R Pfeifer et al. Essays Biochem. 2019.

• ¹ Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA.

• PMID: 31366473
• DOI: 10.1042/EBC20190007

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In many contexts of development, regeneration, or disease such as cancer, a cell squeezes through a dense tissue or a basement membrane, constricting its nucleus. Here, we describe how the severity of nuclear deformation depends on a nucleus' mechanical properties that are mostly determined by the density of chromatin and by the nuclear lamina. We explain how constriction-induced nuclear deformation affects nuclear contents by causing (i) local density changes in chromatin and (ii) rupture of the nuclear lamina and envelope. Both processes mislocalize diffusible nuclear factors including key DNA repair and regulatory proteins. Importantly, these effects of constricted migration are accompanied by excess DNA damage, marked by phosphorylated histone γH2AX in fixed cells. Rupture has a number of downstream consequences that include a delayed cell cycle-consistent with a damage checkpoint-and modulation of differentiation, both of which are expected to affect migration-dependent processes ranging from wound healing to tumorigenic invasion.

Keywords: DNA repair; Nuclear strength; confined migration.

© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

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• Constricted migration increases DNA damage and independently represses cell cycle.

  Pfeifer CR, Xia Y, Zhu K, Liu D, Irianto J, García VMM, Millán LMS, Niese B, Harding S, Deviri D, Greenberg RA, Discher DE. Pfeifer CR, et al. Mol Biol Cell. 2018 Aug 8;29(16):1948-1962. doi: 10.1091/mbc.E18-02-0079. Epub 2018 May 9. Mol Biol Cell. 2018. PMID: 29742017 Free PMC article.

• An absence of lamin B1 in migrating neurons causes nuclear membrane ruptures and cell death.

  Chen NY, Yang Y, Weston TA, Belling JN, Heizer P, Tu Y, Kim P, Edillo L, Jonas SJ, Weiss PS, Fong LG, Young SG. Chen NY, et al. Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25870-25879. doi: 10.1073/pnas.1917225116. Epub 2019 Dec 3. Proc Natl Acad Sci U S A. 2019. PMID: 31796586 Free PMC article.

• Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration.

  Jung HJ, Nobumori C, Goulbourne CN, Tu Y, Lee JM, Tatar A, Wu D, Yoshinaga Y, de Jong PJ, Coffinier C, Fong LG, Young SG. Jung HJ, et al. Proc Natl Acad Sci U S A. 2013 May 21;110(21):E1923-32. doi: 10.1073/pnas.1303916110. Epub 2013 May 6. Proc Natl Acad Sci U S A. 2013. PMID: 23650370 Free PMC article.

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