Nuclear Rupture at Sites of High Curvature Compromises Retention of DNA Repair Factors
| Autor: | Charlotte R. Pfeifer, Cory Alvey, Jiazheng Ji, Kuangzheng Zhu, Roger A. Greenberg, Rachel R. Bennett, Jerome Irianto, Dennis E. Discher, Dazhen Liu, Irena L. Ivanovska, Sangkyun Cho, Yuntao Xia, Andrea J. Liu, Lucas R. Smith |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
animal structures DNA Repair DNA damage DNA repair Cell Biophysics macromolecular substances Matrix (biology) Biology Curvature Medical and Health Sciences Histones 03 medical and health sciences 0302 clinical medicine Report Extracellular medicine Humans Cytoskeleton Research Articles 030304 developmental biology Cell Nucleus 0303 health sciences Chemistry Cell Biology Biological Sciences Lamin Type A Cell biology Cell nucleus 030104 developmental biology medicine.anatomical_structure A549 Cells Lamin 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | The Journal of cell biology, vol 217, iss 11 The Journal of Cell Biology |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2018.11.144 |
| Popis: | Xia et al. show how force probes and cytoskeletal stress can induce nucleus-specific rupture. Rupture correlates with nuclear curvature and is promoted by low lamin A, high actomyosin stress, and stiff ECM. Rupture leads to cytoplasmic mislocalization of DNA repair factors. 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. |
| Databáze: | OpenAIRE |
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