Cyclin A2 binds to Mre11 mRNA to promote Mre11 translation and repair of replication errors.

  • Major finding: Cyclin A2 binds to Mre11 mRNA to promote Mre11 translation and repair of replication errors.

  • Concept: Cyclin A2 loss promotes chromosomal instability and spontaneous and carcinogen-induced tumor development.

  • Impact: Cyclins may play broader cellular roles than previously appreciated.

Cyclin A2 (encoded by CCNA2) is responsible for activating the cyclin-dependent kinases CDK1 and CDK2 to induce S-phase chromosome duplication and initiate mitosis. As both underexpression and overexpression of cyclin A2 have been linked to poor outcome in tumors, the role of cyclin A2 in tumor progression is unclear. Because complete loss of cyclin A2 is embryonically lethal, Kanakkanthara and colleagues developed a hypomorphic Ccna2 allele (Ccna2H) with reduced expression of cyclin A2 to better understand its role in tumorigenesis. Ccna2−/H mice had a marked reduction in cyclin A2 protein in tissues with a high mitotic index but relatively normal levels in tissues with less actively dividing cells. Ccna2−/H mice were more susceptible to spontaneous and carcinogen-induced tumors than Ccna2+/+ mice, indicating that cyclin A2 insufficiency promotes malignant transformation. Mouse embryonic fibroblasts (MEF) from Ccna2−/H mice exhibited increased aneuploidy due to chromosome segregation errors such as lagging chromosomes and chromatin bridges. Additionally, in Ccna2−/H MEFs, DNA replication forks progressed more slowly and stalled more frequently than in Ccna2+/+ MEFs, leading to an increased rate of DNA double-strand breaks. Consistent with these findings, expression of MRE11, a component of the MRN complex that is critical for DSB repair and replication fork restart, was reduced in Ccna2−/H MEFs. Mechanistically, cyclin A2 bound directly to the 3′UTR of Mre11 mRNA in a CDK-independent manner to promote its translation, and thus depletion of cyclin A2 resulted in a reduction in MRE11. Ectopic expression of MRE11 in Ccna2−/H cells rescued double-strand breaks and chromosome defects, suggesting that MRE11 insufficiency is responsible for these effects. In addition to suggesting that cyclin A2 insufficiency promotes tumorigenesis, these findings reveal a previously undescribed function for a cyclin as an RNA-binding protein in addition to its CDK-dependent functions.

Kanakkanthara A, Jeganathan KB, Limzerwala JF, Baker DJ, Hamada M, Nam HJ, et al. Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. Science 2016;353:1549–52.

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