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

Arun Kanakkanthara, Karthik B. Jeganathan, Jazeel F. Limzerwala, Darren J Baker, Masakazu Hamada, Hyun Ja Nam, Willemijn H. Van Deursen, Naomi Hamada, Ryan M. Naylor, Nicole A. Becker, Brian A. Davies, Janine H. Van Ree, Georges Mer, Virginia M Shapiro, L James Maher III, David J Katzmann, Jan Van Deursen

Research output: Contribution to journalArticle

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Abstract

Cyclin A2 activates the cyclin-dependent kinases Cdk1 and Cdk2 and is expressed at elevated levels from S phase until early mitosis. We found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to up-regulate the meiotic recombination 11 (Mre11) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly, cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively and directly binds Mre11 transcripts to mediate polysome loading and translation. These data reveal cyclin A2 as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependent functions with a kinase-independent, RNA binding-dependent role that ensures adequate repair of common replication errors.

Original languageEnglish (US)
Pages (from-to)1549-1552
Number of pages4
JournalScience
Volume353
Issue number6307
DOIs
StatePublished - Sep 30 2016

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Cyclin A2
RNA-Binding Proteins
Protein Biosynthesis
Genetic Recombination
S Phase
Phosphotransferases
Chromosomal Instability
Chromosome Segregation
Polyribosomes
Double-Stranded DNA Breaks
Cyclin-Dependent Kinases
DNA Replication
Mitosis
Up-Regulation
RNA
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. / Kanakkanthara, Arun; Jeganathan, Karthik B.; Limzerwala, Jazeel F.; Baker, Darren J; Hamada, Masakazu; Nam, Hyun Ja; Van Deursen, Willemijn H.; Hamada, Naomi; Naylor, Ryan M.; Becker, Nicole A.; Davies, Brian A.; Van Ree, Janine H.; Mer, Georges; Shapiro, Virginia M; Maher III, L James; Katzmann, David J; Van Deursen, Jan.

In: Science, Vol. 353, No. 6307, 30.09.2016, p. 1549-1552.

Research output: Contribution to journalArticle

Kanakkanthara, A, Jeganathan, KB, Limzerwala, JF, Baker, DJ, Hamada, M, Nam, HJ, Van Deursen, WH, Hamada, N, Naylor, RM, Becker, NA, Davies, BA, Van Ree, JH, Mer, G, Shapiro, VM, Maher III, LJ, Katzmann, DJ & Van Deursen, J 2016, 'Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation', Science, vol. 353, no. 6307, pp. 1549-1552. https://doi.org/10.1126/science.aaf7463
Kanakkanthara, Arun ; Jeganathan, Karthik B. ; Limzerwala, Jazeel F. ; Baker, Darren J ; Hamada, Masakazu ; Nam, Hyun Ja ; Van Deursen, Willemijn H. ; Hamada, Naomi ; Naylor, Ryan M. ; Becker, Nicole A. ; Davies, Brian A. ; Van Ree, Janine H. ; Mer, Georges ; Shapiro, Virginia M ; Maher III, L James ; Katzmann, David J ; Van Deursen, Jan. / Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. In: Science. 2016 ; Vol. 353, No. 6307. pp. 1549-1552.
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