Interplay between the DNA damage proteins MDC1 and ATM in the regulation of the spindle assembly checkpoint [Cell Biology]

February 7th, 2014 by Eliezer, Y., Argaman, L., Kornowski, M., Roniger, M., Goldberg, M.

To avoid genomic instability, cells have developed surveillance mechanisms such as the spindle assembly checkpoint (SAC) and the DNA damage response (DDR). ATM and MDC1 are central players of the cellular response to DNA double-strand breaks. Here we identify a new role for these proteins in the regulation of mitotic progression and in SAC activation. MDC1 localizes at mitotic kinetochores following SAC activation in an ATM-dependent manner. ATM phosphorylates histone H2AX at mitotic kinetochores, and this phosphorylation is required for MDC1 localization at kinetochores. ATM and MDC1 are needed for kinetochore localization of the inhibitory mitotic checkpoint complex (MCC) components, Mad2 and Cdc20, and for the maintenance of the MCC integrity. This probably relies on the interaction of MDC1 with the MCC. In this work we have established that ATM and MDC1 maintain genomic stability not only by controlling the DDR, but also by regulating SAC activation, providing an important link between these two essential biological processes.