|Project Overview:||Catenation of sister chromatids is an inevitable consequence of DNA replication, but needs to be progressively resolved by topoisomerase II throughout S phase, G2 and mitosis. Mechanistically independent catenation checkpoints actively survey the decatenation status of topologically intertwined sister chromatids at two points in the cell cycle: the G2 catenation checkpoint monitors adequate decatenation to enable chromosome condensation in prophase. A subset of chromatid catenation persists until anaphase, before which the Metaphase/Anaphase (M/A) catenation checkpoint monitors decatenation to allow for accurate chromosome segregation in anaphase. If chromosomes are not decatenated before cells complete cytokinesis, chromosome breakage and/or asymmetric segregation ensues, which results in chromosomal translocations, aneuploidy through these non-disjunctional errors or polyploidy in the case of cytokinesis failure. These chromosome aberrations have been documented in almost all tumour types and could at least in part be due to inefficient decatenation checkpoints. A deficiency in the G2 catenation checkpoint has been detected in breast, bladder and lung cancer cells and might thus represent a general feature of malignancy. It is anticipated that transformed cells, which have acquired a loss of function of the G2 checkpoint, rely far more than normal cells on the subsequent M/A catenation checkpoint to avoid catastrophic cell division. Nicola Brownlow in the Parker laboratory has shown that the M/A catenation checkpoint is dependent on PKC? and that cancer cells with a defective G2 catenation checkpoint become reliant on PKC? as PKC? knock-down or inhibition of PKC? impairs cytokinesis of these compromised cells. This PKC? dependency of cytokinesis could be exploited for the targeted therapy of G2 checkpoint-defective cancer cells using PKC? inhibitors.|
|Screener:||Katharina Deiss (Parker Lab).
Extension:3505, Rm 203
|Publications:||A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest.. Deiss et al., 2019
|Project Start Date:||Nov 2013|