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bioRxiv · 10.1101/2022.10.26.513831

A SOD1-dependent mitotic DNA damage checkpoint

Gatenby, R. J.·Li, N.·Lata, P.·Walne, T.·Tufail, A.·Breitweiser, A.·Thompson, R. H.
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Abstract

In the event of DNA damage, the cell cycle can be slowed or halted to allow for DNA repair. The mechanisms by which this occurs are well-characterised in interphase, although the mechanisms underpinning mitosis slowing in response to damage are unclear. Canonical checkpoints and DNA repair pathways are largely repressed in mitosis, and whilst there is some level of mitotic DNA synthesis and repair, the bulk of DNA damage is processed for post-mitotic repair. How the decision is made between mitotic DNA repair and post-mitotic DNA repair is not known. We have identified the antioxidant enzyme Superoxide Dismutase 1 (SOD1) as an essential factor mediating delayed mitotic progression in response to DNA damage and replication stress. Cells depleted of SOD1 no longer exhibit DNA damage dependent mitotic delay, and display increased levels of damaged centromeres and mitotic defects. Whilst reactive oxygen species (ROS)-inducing agents also lead to SOD1-dependent mitotic delay, intracellular ROS levels do not correlate with mitotic arrest. SOD1 appears to play an important role in DNA repair in interphase and is recruited to the nucleus in response to DNA damage. In addition to control of mitotic progression in response to genotoxic stress, SOD1 also plays a major role in mitotic DNA synthesis. SOD- depleted cells show reduced levels of mitotic EdU incorporation in response to either replication stress or DNA breaks, seemingly in tandem with Rad51 andSOD1-depletion induced mitotic progression in the presence of DNA breaks is Rad52-dependent. We suggest that there are two responses to DNA breaks in mitosis; either arrest and mitotic repair or progression and post-mitotic repair; and these two pathways exist in a fine balance, controlled by a signaling cascade involving SOD1.

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Gatenby, R. J., Li, N., Lata, P., Walne, T., Tufail, A., Breitweiser, A., Thompson, R. H.. 2022-10-26. A SOD1-dependent mitotic DNA damage checkpoint. https://doi.org/10.1101/2022.10.26.513831

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