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Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation

Arun Kanakkanthara1, Karthik B Jeganathan1, Jazeel F Limzerwala2

  • 1Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.

Science (New York, N.Y.)
|October 7, 2016
PubMed

Insights

Cyclin A2 deficiency causes chromosomal instability and tumors by impairing DNA repair. This occurs because cyclin A2 is essential for Mre11 nuclease translation, ensuring proper replication fork resolution and DNA break repair.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cyclin A2 activates cyclin-dependent kinases (Cdk1 and Cdk2), crucial for cell cycle progression.
  • Elevated cyclin A2 levels are observed from S phase through early mitosis.
  • Loss of cyclin A2 leads to chromosomal instability and tumor predisposition in mice.

Purpose of the Study:

  • To investigate the underlying mechanisms of chromosomal instability in cyclin A2-deficient mice.
  • To elucidate the role of cyclin A2 in DNA replication and repair processes.
  • To identify novel functions of cyclin A2 beyond its kinase activation.

Main Methods:

  • Analysis of mutant mice lacking cyclin A2.
  • Assessment of chromosomal stability and tumor formation.
  • Investigation of meiotic recombination 11 (Mre11) nuclease expression and function.
  • Characterization of cyclin A2's interaction with Mre11 transcripts using its RNA binding domain.

Main Results:

  • Cyclin A2 deficiency results in chromosomal instability and tumor susceptibility.
  • Impaired Mre11 nuclease up-regulation in S phase leads to stalled replication fork resolution issues.
  • Double-stranded DNA breaks accumulate, and sister chromosome segregation is improper.
  • Cyclin A2 directly binds Mre11 transcripts via its C-terminal RNA binding domain, promoting polysome loading and translation.

Conclusions:

  • Cyclin A2 is a critical regulator of DNA replication fidelity.
  • It possesses both kinase-dependent and kinase-independent functions.
  • The kinase-independent role involves RNA binding to control Mre11 translation, ensuring DNA repair.
  • This dual mechanism highlights cyclin A2's importance in preventing replication errors and maintaining genomic stability.

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