Abstract
The budding yeast G-tail binding complex CST (Cdc13-Stn1-Ten1) is crucial for both telomere protection and replication. Previous studies revealed a family of Cdc13 orthologues (Cdc13A) in Candida species that are unusually small but are nevertheless responsible for G-tail binding and the regulation of telomere lengths and structures. Here we report the identification and characterization of a second family of Cdc13-like proteins in the Candida clade, named Cdc13B. Phylogenetic analysis and sequence alignment indicate that Cdc13B probably arose through gene duplication prior to Candida speciation. Like Cdc13A, Cdc13B appears to be essential. Deleting one copy each of the CDC13A and CDC13B genes caused a synergistic effect on aberrant telomere elongation and t-circle accumulation, suggesting that the two paralogues mediate overlapping and nonredundant functions in telomere regulation. Interestingly, Cdc13B utilizes its C-terminal OB-fold domain (OB4) to mediate self-association and binding to Cdc13A. Moreover, the stability of the heterodimer is evidently greater than that of either homodimer. Both the Cdc13 A/A homodimer and A/B heterodimer, but not the B/B homodimer, recognized the telomere G-tail repeat with high affinity and sequence specificity. Our results reveal novel evolutionary elaborations of the G-tail-binding protein in Saccharomycotina yeast, suggesting a drastic remodeling of CDC13 that entails gene duplication, fusion, and functional specialization. The repeated and independent duplication of G-tail-binding proteins such as Cdc13 and Pot1 hints at the evolutionary advantage of having multiple G-tail-binding proteins.
Highlights
Cdc13 in Candida species is small and missing conserved domains
We showed that the Candida albicans Cdc13 (CaCdc13) associates with telomere DNA in vivo and is required for normal telomere length regulation [18]
We further demonstrated high affinity telomere DNA binding by the Candida tropicalis Cdc13 (CtCdc13) in vitro and found that this binding activity requires dimerization of CtCdc13 through its OB4 domain [18]
Summary
Cdc in Candida species is small and missing conserved domains. Results: A second Cdc homologue (Cdc13B) was shown to form heterodimers with Cdc and to mediate overlapping functions in telomere protection. We and others have identified and characterized a family of Cdc homologues in Candida species that are noticeably smaller than ScCdc13 These homologues lack the N-terminal half of the prototypical Cdc and contain just two OB-fold domains: DBD and OB4 (Fig. 1A) [11, 16, 17]. The lack of the N-terminal half of Cdc poses a conundrum, indicating that the functions mediated by the missing domains such as Pol binding and telomerase recruitment must either be absent or taken over by other proteins in Candida species. The Cdc13A/ Cdc13B dimer (A/B dimer) binds telomere G-tails with high affinity and sequence specificity in vitro, suggesting that it could constitute the predominant form of Cdc in vivo. Our findings provide insights on the assembly and DNA binding mechanisms of CST as well as its unusual elaboration in a fungal branch
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