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Chromosome cohesion is regulated by a clock gene paralogue TIM-1

Abstract

Faithful transmission of the genome requires that a protein complex called cohesin establishes and maintains the regulated linkage between replicated chromosomes before their segregation1,2. Here we report the unforeseen participation of Caenorhabditis elegans TIM-1, a paralogue of the Drosophila clock protein TIMELESS, in the regulation of chromosome cohesion. Our biochemical experiments defined the C. elegans cohesin complex and revealed its physical association with TIM-1. Functional relevance of the interaction was demonstrated by aberrant mitotic chromosome behaviour, embryonic lethality and defective meiotic chromosome cohesion caused by the disruption of either TIM-1 or cohesin. TIM-1 depletion prevented the assembly of non-SMC (structural maintenance of chromosome) cohesin subunits onto meiotic chromosomes; however, unexpectedly, a partial cohesin complex composed of SMC components still loaded. Further disruption of cohesin activity in meiosis by the simultaneous depletion of TIM-1 and an SMC subunit decreased homologous chromosome pairing before synapsis, revealing a new role for cohesin in metazoans. On the basis of comparisons between TIMELESS homologues in worms, flies and mice, we propose that chromosome cohesion, rather than circadian clock regulation, is the ancient and conserved function for TIMELESS-like proteins.

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Figure 1: C. elegans TIM-1, a paralogue of the circadian clock protein TIMELESS, associates with the cohesin complex.
Figure 2: TIM-1, like cohesin subunits, is essential for mitotic chromosome segregation in somatic and germline tissues.
Figure 3: tim-1 mutants are defective in meiotic chromosome cohesion.
Figure 4: TIM-1 is restricted to pre-meiotic nuclei, unlike meiotic cohesin, which localizes between sister chromatids throughout meiotic prophase.
Figure 5: Loss of tim-1 function preferentially disrupts the loading or stability of non-SMC cohesin subunits.

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Acknowledgements

We thank D. King for the MALDI–MS analyses, M. Ralston for advice on statistical methods, J. Loidl, A. Villeneuve and Y. Kohara for useful reagents, G. Csankovszki for the RNA blot, M. Colaiacovo and A. Villeneuve for discussions, and T. Cline, A. Severson and C. Tsai for comments on the manuscript. This work was supported by the Leukemia and Lymphoma Society (R.C.C.), the American Cancer Society (D.P.) and the National Institutes of Health (A.E.R.). B.J.M. is an investigator and R.C.C. an associate of the Howard Hughes Medical Institute.

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Correspondence to Barbara J. Meyer.

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Chan, R., Chan, A., Jeon, M. et al. Chromosome cohesion is regulated by a clock gene paralogue TIM-1. Nature 423, 1002–1009 (2003). https://doi.org/10.1038/nature01697

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