The evolution of metazoan shelterin

Abstract

The mammalian telomeric shelterin complex—comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1—blocks the DNA damage response at chromosome ends and interacts with telomerase and the CST complex to regulate telomere length. The evolutionary origins of shelterin are unclear, partly because unicellular organisms have distinct telomeric proteins. Here, we describe the evolution of metazoan shelterin, showing that TRF1 emerged in vertebrates upon duplication of a TRF2-like ancestor. TRF1 and TRF2 diverged rapidly during vertebrate evolution through the acquisition of new domains and interacting factors. Vertebrate shelterin is also distinguished by the presence of an HJRL domain in the split C-terminal OB fold of POT1, whereas invertebrate POT1s carry inserts of variable nature. Importantly, the data reveal that, apart from the primate and rodent POT1 orthologs, all metazoan POT1s are predicted to have a fourth OB fold at their N termini. Therefore, we propose that POT1 arose from a four-OB-fold ancestor, most likely an RPA70-like protein. This analysis provides insights into the biology of shelterin and its evolution from ancestral telomeric DNA-binding proteins.

The non-telomeric evolutionary trajectory of TRF2 in zebrafish reveals its specific roles in neurodevelopment and aging

“…Noteworthy, a parallel experiment with purified telobox of zfTRF1 also exhibits a specific telomeric DNA binding but with a smeary migration of the complexes suggesting an unstable interaction (Figure 2B ). This is in agreement with a recent publication showing that zfTRF1 binds telomeric DNA when expressed in mouse cells ( 28 ). Overall, we conclude that zfTRF2 in zebrafish cells maintain its intrinsic capacity to bind telomeres.…”

Ustilago maydis telomere protein Pot1 harbors an extra N-terminal OB fold and regulates homology-directed DNA repair factors in a dichotomous and context-dependent manner

“…Thus, most basidiomycete Pot1s appear to harbor four OB-fold domains (designated OB-N, OB1, OB2 and OB3). Interestingly, Myler et al recently showed that this is true for the majority of metazoan POT1s as well [27]. In support of common ancestry, we found that the two groups of OB-Ns from basidiomycetes and metazoan Pot1s align well to each other (S1 Fig).…”

“…Based on structural and functional considerations, it has been argued that RPA, CST and POT1-TPP1 may represent ancient paralogs (i.e., RPA1 ≈ CTC1 ≈ POT1 and RPA2 ≈ STN1 ≈ TPP1) and accordingly may share more structural and functional similarities than hitherto realized [17]. Our analysis, coupled with that by Myler et al [27], indicates that the common ancestor of fungal and metazoan POT1 probably contained four OB-folds and utilized the two central OBs (OB1 and OB2) for high affinity DNA-binding, just like RPA1. This notion reinforces the growing evidence for structural similarities – and hence evolutionary kinship – between these OB-fold-rich complexes (S9 Fig).…”

“…contain just three OB folds (Fig 1A). Because phylogenomic analysis indicates that Chytridiomycota and Zoopagomycota represent deeper fungal lineages than Basidiomycota, it is possible that OB-N might have been independently lost in multiple fungal branches [28], just as it was lost in selected metazoans [27]. In contrast to OB-N, the OB3 domain is evidently well conserved in all fungal phyla, except for the loss of Zinc-binding residues in ascomycetes Pot1 (S1 Fig).…”

“…Herein we report our investigation of U. maydis Pot1, the conserved and essential G-strand binding protein. Compared to the well characterized mammalian and fission yeast Pot1 orthologs, Um Pot1 harbors an extra N-terminal OB fold domain (OB-N), which was recently shown to be conserved in most metazoan Pot1 proteins [27]. Functional analysis in U. maydis revealed multi-faceted, Pot1-dependent effects of DNA repair factors on telomere regulation.…”