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 S. Shapiro; L. James Maher; David J. Katzmann; Jan M. Van Deursen

doi:10.1126/science.aaf7463

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 S. Shapiro, L. James Maher, David J. Katzmann, Jan M. Van Deursen

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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 language	English (US)
Pages (from-to)	1549-1552
Number of pages	4
Journal	Science
Volume	353
Issue number	6307
DOIs	https://doi.org/10.1126/science.aaf7463
State	Published - Sep 30 2016

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Kanakkanthara, A., Jeganathan, K. B., Limzerwala, J. F., Baker, D. J., Hamada, M., Nam, H. J., Van Deursen, W. H., Hamada, N., Naylor, R. M., Becker, N. A., Davies, B. A., Van Ree, J. H., Mer, G., Shapiro, V. S., Maher, L. J., Katzmann, D. J., & Van Deursen, J. M. (2016). Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. Science, 353(6307), 1549-1552. https://doi.org/10.1126/science.aaf7463

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, VS , Maher, LJ, Katzmann, DJ & Van Deursen, JM 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

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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.",

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

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AU - Baker, Darren J.

AU - Hamada, Masakazu

AU - Nam, Hyun Ja

AU - Van Deursen, Willemijn H.

AU - Hamada, Naomi

AU - Naylor, Ryan M.

AU - Becker, Nicole A.

AU - Davies, Brian A.

AU - Van Ree, Janine H.

AU - Mer, Georges

AU - Shapiro, Virginia S.

AU - Maher, L. James

AU - Katzmann, David J.

AU - Van Deursen, Jan M.

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AB - 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.

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

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