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Rescue of DNA damage in cells after constricted migration reveals bimodal mechano-regulation of cell cycle

View ORCID ProfileYuntao Xia, Charlotte R. Pfeifer, Kuangzheng Zhu, Jerome Irianto, Dazhen Liu, Kalia Pannell, Emily J. Chen, Lawrence J. Dooling, Roger A. Greenberg, Dennis E. Discher
doi: https://doi.org/10.1101/508200
Yuntao Xia
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • ORCID record for Yuntao Xia
Charlotte R. Pfeifer
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
3Graduate Group / Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA 19104, USA
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Kuangzheng Zhu
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
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Jerome Irianto
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
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Dazhen Liu
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
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Kalia Pannell
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
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Emily J. Chen
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
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Lawrence J. Dooling
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
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Roger A. Greenberg
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
4Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Dennis E. Discher
1Physical Sciences Oncology Center at Penn (PSOC@Penn), University of Pennsylvania, Philadelphia, PA 19104, USA
2Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104, USA
3Graduate Group / Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA 19104, USA
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Abstract

Migration through constrictions can clearly rupture nuclei and mis-localize nuclear proteins but damage to DNA remains uncertain as does any effect on cell cycle. Here, myosin-II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent delay in cell cycle is unaffected. Co-overexpression of multiple DNA repair factors and antioxidant inhibition of break formation also have partial effects, independent of rupture. However, there seems to be a bimodal dependence of cell cycle on DNA damage. Migration through custom-etched pores yields the same bimodal, with ~4-μm pores causing intermediate levels of damage and cell cycle delay. Micronuclei (generated in faulty division) of the smallest diameter appear similar to ruptured nuclei, with high DNA damage and entry of chromatin-binding cGAS (cyclic-GMP-AMP-synthase) from cytoplasm but low repair factor levels. Increased genomic variation after constricted migration is quantified in expanding clones and is consistent with (mis)repair of excess DNA damage and subsequent proliferation.

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Posted December 30, 2018.
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Rescue of DNA damage in cells after constricted migration reveals bimodal mechano-regulation of cell cycle
Yuntao Xia, Charlotte R. Pfeifer, Kuangzheng Zhu, Jerome Irianto, Dazhen Liu, Kalia Pannell, Emily J. Chen, Lawrence J. Dooling, Roger A. Greenberg, Dennis E. Discher
bioRxiv 508200; doi: https://doi.org/10.1101/508200
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Rescue of DNA damage in cells after constricted migration reveals bimodal mechano-regulation of cell cycle
Yuntao Xia, Charlotte R. Pfeifer, Kuangzheng Zhu, Jerome Irianto, Dazhen Liu, Kalia Pannell, Emily J. Chen, Lawrence J. Dooling, Roger A. Greenberg, Dennis E. Discher
bioRxiv 508200; doi: https://doi.org/10.1101/508200

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