ATR prevents cells entering mitosis with excess unreplicated DNA and is required for the Abscission Checkpoint
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Maintaining genome integrity is an essential requirement for cells and a tightly regulated DNA damage response (DDR) is required to maintain viability of the cell and prevent disease. ATM and ATR are key regulators in the DDR involved in sensing, signalling the damage and DNA repair. Initially, we focus on the centromere and centrosome and identify potential interactors of ATM and ATR. Two microtubule end binding proteins CLASP1 and CLASP2 stabilise microtubules and influence the dynamic properties of the spindle. Following DNA damage we observe an increase in microtubule stabilisation, which is dependent on PIK kinase activity suggesting new roles for the CLASP proteins in the DDR. We also investigate the essential role of the PIK kinase protein ATR during unperturbed growth in vertebrate cells. Without Atr cells cycle more rapidly and continue to replicate the DNA closer to chromosome condensation during mitosis. This creates further problems for the cells with chromatid gaps and breaks in metaphase chromosomes and increased segregation problems in anaphase. At cytokinesis Atr-depleted cells also show a higher frequency of cells failing to separate. Partial Cdk1 inhibition rescues cell death by slowing down the cell cycle, ensuring a more accurate cytokinesis. Altogether, our data suggests an essential role for Atr in regulating the S-M transition and delaying the onset of mitosis when replication has not been completed. We also examine a role for ATR in cytokinesis and ensuring timely chromosome segregation before the final abscission between daughter cells. Stable actin patches, indicative of an active abscission checkpoint are reduced in Atr-depleted conditions, and increase following Atm inhibition. Our observations suggest novel roles for the PIK kinases in responding to DNA lingering in the intercellular canal ensuring successful cytokinesis
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