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DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability

Zhiguo Li1, Chen Shao1, Yifan Kong2

  • 1Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.

Molecular and Cellular Biology
|February 15, 2017
PubMed

Insights

Mediator of DNA damage checkpoint 1 (MDC1) has a newly discovered role in cell division and genomic stability, independent of DNA damage response pathways. This finding reveals MDC1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Mediator of DNA damage checkpoint 1 (MDC1) is known for its role in DNA damage response (DDR).
  • Its functions beyond DDR are not well understood.

Purpose of the Study:

  • To investigate novel functions of MDC1 beyond its established role in DNA damage.
  • To explore the role of phosphorylated MDC1 in mitotic progression and genomic stability.

Main Methods:

  • Investigated MDC1 as a target of Polo-like kinase 1 (Plk1).
  • Analyzed the localization of phosphorylated MDC1 in various cellular compartments.
  • Utilized knockdown and phosphorylation abrogation techniques in cellular and animal models.

Main Results:

  • Phosphorylated MDC1 functions independently of ATM and DNA damage.
  • MDC1 localizes to nuclear envelopes, centrosomes, kinetochores, and midbodies during mitosis.
  • MDC1 knockdown or impaired Plk1 phosphorylation delays prometaphase-metaphase transition.
  • Reduced MDC1 levels in mice lead to increased spontaneous tumors in aged animals.

Conclusions:

  • MDC1 plays a critical role in mitotic progression and genomic stability through a DDR-independent pathway.
  • Phosphorylation by Plk1 is crucial for MDC1's novel functions.
  • MDC1's role extends beyond DNA repair to fundamental cell cycle regulation and tumor suppression.
Keywords:
MDC1Plk1genomic instabilitymitosisphosphorylation

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