title: Interplay between the DNA damage proteins MDC1 and ATM in the regulation of the spindle assembly checkpoint.
abstract: To avoid genomic instability, cells have developed surveillance mechanisms such as the spindle assembly checkpoint (SAC) and the DNA damage response. 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 components, Mad2 and Cdc20, and for the maintenance of the mitotic checkpoint complex 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 DNA damage response, but also by regulating SAC activation, providing an important link between these two essential biological processes.
authors: From the Department of Genetics, The Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.
authors: Yifat
authors: Y
authors: Eliezer
authors: Liron
authors: L
authors: Argaman
authors: Maya
authors: M
authors: Kornowski
authors: Maayan
authors: M
authors: Roniger
authors: Michal
authors: M
authors: Goldberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins / Q000032:analysis / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage; D006657:Histones / Q000032:analysis / Q000378:metabolism; D006801:Humans; D018386:Kinetochores / Q000378:metabolism* / Q000648:ultrastructure; D059566:M Phase Cell Cycle Checkpoints; D008938:Mitosis; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Cell Cycle; Checkpoint Control; DNA Damage Response; Kinetochore; Mitosis