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Interplay between the DNA damage proteins MDC1 and ATM in the regulation of the spindle assembly checkpoint

Yifat Eliezer1, Liron Argaman, Maya Kornowski

  • 1From the Department of Genetics, The Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.

The Journal of Biological Chemistry
|February 11, 2014
PubMed

Insights

ATM and MDC1 proteins regulate cell division by activating the spindle assembly checkpoint (SAC). This ensures genomic stability by linking DNA damage response to SAC activation.

Area of Science:

  • Cell Biology
  • Genetics
  • Molecular Biology

Background:

  • Genomic instability is prevented by surveillance mechanisms like the spindle assembly checkpoint (SAC) and DNA damage response.
  • ATM and MDC1 are key proteins involved in the cellular response to DNA double-strand breaks.

Purpose of the Study:

  • To investigate the role of ATM and MDC1 in regulating mitotic progression and SAC activation.
  • To elucidate the molecular mechanisms underlying the interaction between DNA damage response and SAC.

Main Methods:

  • Immunofluorescence microscopy to observe protein localization at kinetochores.
  • Western blotting to assess protein phosphorylation and complex integrity.
  • Genetic manipulation to study the requirement of ATM and MDC1 in SAC function.

Main Results:

  • MDC1 localizes to mitotic kinetochores in an ATM-dependent manner following SAC activation.
  • ATM phosphorylates histone H2AX at kinetochores, which is crucial for MDC1 recruitment.
  • ATM and MDC1 are essential for the kinetochore localization and stability of the mitotic checkpoint complex (MCC) components Mad2 and Cdc20.

Conclusions:

  • ATM and MDC1 play a novel role in regulating mitotic progression and SAC activation.
  • These proteins maintain genomic stability by coordinating the DNA damage response with SAC activation.
  • This study reveals a critical link between DNA damage response and the spindle assembly checkpoint.
Keywords:
Cell CycleCheckpoint ControlDNA Damage ResponseKinetochoreMitosis

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