RPA phosphorylation facilitates mitotic exit in response to mitotic DNA damage.

Proceedings of the National Academy of Sciences of the United States of America
Rachel William AnanthaJames A Borowiec

Abstract

Human replication protein A (RPA) becomes phosphorylated on the RPA2 subunit by cyclin B-Cdc2 during mitosis, although the functional role of this modification is unclear. We find that this modification stimulates RPA2 to become hyperphosphorylated in response to mitotic DNA damage caused by bleomycin treatment. Cells in which endogenous RPA2 was replaced by a mutant subunit lacking both Cdc2 sites had a significant defect in mitotic release into a 2N G(1) phase after exposure to bleomycin. An increased percentage of these mutant cells also was positive initially for cyclin B expression and BubR1 chromatin staining, indicative of an extended spindle assembly checkpoint. The mutant cells that experienced mitotic DNA damage also underwent apoptosis at higher levels than cells expressing the WT subunit. Even so, we did not find the mutation had any dramatic effects on the level of DNA repair in mitosis. Cells lacking ATM (a checkpoint factor and RPA2 kinase) also were severely defective in mitotic exit and were unable to support RPA hyperphosphorylation after mitotic DNA damage. Although checkpoint 1 effector kinase (Chk1) had a more complex role, inhibition of Chk1 activity with UCN-01 also reduced mitotic exit. Chk1 activation a...Continue Reading

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Citations

Feb 16, 2010·Nature Structural & Molecular Biology·Dong-Hyun LeeDipanjan Chowdhury
Sep 18, 2009·The Journal of Biological Chemistry·Jingsong Yuan, Junjie Chen
Sep 6, 2012·The Journal of Biological Chemistry·Laura A Lindsey-BoltzAziz Sancar
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Dec 23, 2016·Nature Cell Biology·Nicole Hustedt, Daniel Durocher
Aug 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Kezhen YangJie Le
May 29, 2021·Planta·Supriyo ChowdhurySupriya Chakraborty

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