Nuclear rupture at sites of high curvature compromises retention of DNA repair factors

Yuntao Xia, Irena L. Ivanovska, Kuangzheng Zhu, Lucas Smith, Jerome Irianto, Charlotte R. Pfeifer, Cory M. Alvey, Jiazheng Ji, Dazhen Liu, Sangkyun Cho, Rachel R. Bennett, Andrea J. Liu, Roger A. Greenberg, Dennis E. Discher

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix—all of which sustain forces, but their relationships to DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization of multiple DNA repair factors correlates with high nuclear curvature imposed by an external probe or by cell attachment to either aligned collagen fibers or stiff matrix. Mislocalization is greatly enhanced by lamin A depletion, requires hours for nuclear reentry, and correlates with an increase in pan-nucleoplasmic foci of the DNA damage marker γH2AX. Excess DNA damage is rescued in ruptured nuclei by cooverexpression of multiple DNA repair factors as well as by soft matrix or inhibition of actomyosin tension. Increased contractility has the opposite effect, and stiff tumors with low lamin A indeed exhibit increased nuclear curvature, more frequent nuclear rupture, and excess DNA damage. Additional stresses likely play a role, but the data suggest high curvature promotes nuclear rupture, which compromises retention of DNA repair factors and favors sustained damage.

Original languageEnglish (US)
Pages (from-to)3796-3808
Number of pages13
JournalJournal of Cell Biology
Volume217
Issue number11
DOIs
StatePublished - Nov 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Xia, Y., Ivanovska, I. L., Zhu, K., Smith, L., Irianto, J., Pfeifer, C. R., Alvey, C. M., Ji, J., Liu, D., Cho, S., Bennett, R. R., Liu, A. J., Greenberg, R. A., & Discher, D. E. (2018). Nuclear rupture at sites of high curvature compromises retention of DNA repair factors. Journal of Cell Biology, 217(11), 3796-3808. https://doi.org/10.1083/jcb.201711161