title: Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation.
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.
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Kanakkanthara
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Karthik B
authors.initials: KB
authors.lastname: Jeganathan
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jazeel F
authors.initials: JF
authors.lastname: Limzerwala
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hamada
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Hyun-Ja
authors.initials: HJ
authors.lastname: Nam
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Willemijn H
authors.initials: WH
authors.lastname: van Deursen
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hamada
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Naylor
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Becker
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Davies
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Janine H
authors.initials: JH
authors.lastname: van Ree
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Georges
authors.initials: G
authors.lastname: Mer
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Shapiro
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: L James
authors.initials: LJ
authors.lastname: Maher
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Katzmann
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA. vandeursen.jan@mayo.edu.
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000235:genetics
chemical_list: C508184:CCNA2 protein, mouse; D056751:Cyclin A2; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016203:CDC2 Protein Kinase; D000076228:MRE11 Homologue Protein; C521052:Kif11 protein, mouse; D016547:Kinesins; D045643:DNA Repair Enzymes