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Evolution of the Cdk-activator Speedy/RINGO in vertebrates

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Abstract

Successful completion of the cell cycle relies on the precise activation and inactivation of cyclin-dependent kinases (Cdks) whose activity is mainly regulated by binding to cyclins. Recently, a new family of Cdk regulators termed Speedy/RINGO has been discovered, which can bind and activate Cdks but shares no apparent amino acid sequence homology with cyclins. All Speedy proteins share a conserved domain of approximately 140 amino acids called “Speedy Box”, which is essential for Cdk binding. Speedy/RINGO proteins display an important role in oocyte maturation in Xenopus. Interestingly, a common feature of all Speedy genes is their predominant expression in testis suggesting that meiotic functions may be the most important physiological feature of Speedy genes. Speedy homologs have been reported in mammals and can be traced back to the most primitive clade of chordates (Ciona intestinalis). Here, we investigated the evolution of the Speedy genes and have identified a number of new Speedy/RINGO proteins. Through extensive analysis of numerous species, we discovered diverse evolutionary histories: the number of Speedy genes varies considerably among species, with evidence of substantial gains and losses. Despite the interspecies variation, Speedy is conserved among most species examined. Our results provide a complete picture of the Speedy gene family and its evolution.

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Acknowledgments

We are thankful to Kaldis laboratory members for support, discussions, and comments on the manuscript. We are grateful to Ernesto Guccione and Antonis Giannakakis for providing cDNA from human tissues and Alice Tay and the DNA Sequencing Facility for sequencing. This work was supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.

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Author notes

  1. Xinde Zheng

    Present address: The Salk Institute, La Jolla, CA, USA

Authors and Affiliations

  1. Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore

    Sangeeta Chauhan, Xinde Zheng, Yue Ying Tan, Boon-Hui Tay, Shuhui Lim, Byrappa Venkatesh & Philipp Kaldis

  2. Department of Pediatrics, National University of Singapore (NUS), Singapore, 119228, Singapore

    Byrappa Venkatesh

  3. Department of Biochemistry, National University of Singapore (NUS), Singapore, 117597, Republic of Singapore

    Philipp Kaldis

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  1. Sangeeta Chauhan
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Correspondence to Byrappa Venkatesh or Philipp Kaldis.

Electronic supplementary material

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18_2012_1050_MOESM1_ESM.jpg

Supplementary Figure 1A. Localization of different SpeedyB2 and B2-like genes on human chromosome 7 Schematic diagram of chromosome 7, copied from UCSC Genome browser, Human Feb. 2009 (GRch37/hg19). Region 7q11.23 and 7q22.1 are zoomed out and modified to show the copy number variations and localization of Speedy gene on chromosome 7 (not to scale). The WBSCR gene is highlighted to indicate its vicinity to the SpeedyB2 genes. (JPEG 845 kb)

18_2012_1050_MOESM2_ESM.jpg

Supplementary Figure 1B. Localization of different SpeedyB2 and B2-like genes on human chromosome 7 Schematic diagram of region 7q11.23, a region known for high copy number variations, taken from UCSC Genome browser, Human Feb. 2009 (GRch37/hg19). Position of SpeedyE3, SpeedyE5, SpeedyE8P (SpeedyB2 and B2-like genes) are highlighted with red boxes. Multiple copies of WBSCR and GTF2IRD2 genes in region 7q11.23 are shown. (JPEG 907 kb)

18_2012_1050_MOESM3_ESM.jpg

Supplementary Figure 1C. Localization of different SpeedyB2 and B2-like genes on human chromosome 7 A Schematic diagram of region 7q22.1, taken from UCSC Genome browser, Human Feb. 2009 (GRch37/hg19). Position of SpeedyB2–like1 (SpeedyE6/E2L) is highlighted in red. Multiple copies of POLRJ2 (yellow), RASA4 (purple), UPK3BL (blue), and BC041025 (green) genes in region 7q22.1 are shown. (JPEG 783 kb)

18_2012_1050_MOESM4_ESM.jpg

Supplementary Figure 2. Conserved sequences in the SpeedyB1 locus in mouse and human. VISTA plot displaying the extent of sequence conservation in the genomic regions of mouse SpeedyB1a, SpeedyB1b, and human SpeedyB1. MULTI-LAGAN alignment was performed using mouse SpeedyB1a as the base sequence. A higher conservation was found between mouse SpeedyB1a and SpeedyB1b than with human SpeedyB1. Conserved regions in the UTR are shown in cyan, introns in pink, and exons in purple. (JPEG 4969 kb)

18_2012_1050_MOESM5_ESM.jpg

Supplementary Figure 3. Conserved sequences in human SpeedyB2 genes. VISTA plot displaying the extent of conservation in the genomic regions of the human SpeedyB2, SpeedyB2-like1 and SpeedyB2-like2 genes. MULTI-LAGAN was performed using SpeedyB2-like1 as the base sequence. A high level of conservation is evident across UTR, introns and exons. (JPEG 662 kb)

18_2012_1050_MOESM6_ESM.jpg

Supplementary Figure 4. Sequence alignment of human SpeedyB2, SpeedyB2-like1, and SpeedyB2-like2 proteins highlighting repetitive sequences. Sequence alignment of human SpeedyB2, SpeedyB2-like1, and SpeedyB2-like2 proteins. A stretch of repetitive sequence (72 amino acid) is highlighted in purple and green. The number of repeats is indicated on top of the sequence alignment. For convenience, only one complete repeat is shown (repeat 1). Repeats 2 and 5 are only partly shown while repeats 3 and 4 are entirely removed. SpeedyB2-like1 and 2 display two repeats only: repeat 1 (same as repeat 1 of SpeedyB2) and repeat 2 (yellow box). Area marked with dashed line indicates the absence of extra repeats (3-5) in SpeedyB2-like1 and 2. (JPEG 2078 kb)

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Chauhan, S., Zheng, X., Tan, Y.Y. et al. Evolution of the Cdk-activator Speedy/RINGO in vertebrates. Cell. Mol. Life Sci. 69, 3835–3850 (2012). https://doi.org/10.1007/s00018-012-1050-1

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