Dataset Information

Selective constraint and the evolution of the RNA polymerase II C-Terminal Domain.

ABSTRACT: The C-Terminal Domain (CTD) of the large subunit (Rpb1) of RNA Polymerase II has a Tyrosine-Serine-Proline-Threonine-Serine-Proline-Serine repeat structure in many eukaryotes. Chemical modifications of these residues play a central role in the regulation and coordination of the events of transcription. However, substantial variability in the presence and regularity of repeat arrays exists between eukaryote taxa. Following a survey of CTD structure from diverse eukaryote species, two hypotheses were tested relating to repeat structure and the action of selection on the CTD. First, it was found that degenerated repeat structure is associated with lower serine and proline frequencies in some eukaryote taxa but not in others. Second, maximum likelihood models of the evolution of Rpb1 in a number of species groups found that purifying selection on the non-repetitive CTD of several Leishmania species was substantially lower than for the rest of Rpb1, whereas purifying selection in a number of species groups containing repeat arrays was usually as high or nearly as high as for the rest of Rpb1. Characterization of CTD structure for a larger number of species than has been completed previously also revealed a greater diversity of CTD structures in eukaryotes than previously known, along with loss of repeat structure in the animals and fungi, two taxa where it has not previously been known. These results suggest that loss of CTD repeat structure has been an important aspect of RNA Polymerase II evolution in diverse eukaryotes.

SUBMITTER: Stump AD

PROVIDER: S-EPMC3646058 | biostudies-literature | 2013 Mar-Apr

REPOSITORIES: biostudies-literature

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Selective constraint and the evolution of the RNA polymerase II C-Terminal Domain.

Stump Aram D AD Ostrozhynska Khrystyna K

Transcription 20130214 2

The C-Terminal Domain (CTD) of the large subunit (Rpb1) of RNA Polymerase II has a Tyrosine-Serine-Proline-Threonine-Serine-Proline-Serine repeat structure in many eukaryotes. Chemical modifications of these residues play a central role in the regulation and coordination of the events of transcription. However, substantial variability in the presence and regularity of repeat arrays exists between eukaryote taxa. Following a survey of CTD structure from diverse eukaryote species, two hypotheses w ...[more]

PMID: 23412361

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Project description:BackgroundRPB1, the largest subunit of RNA polymerase II, contains a highly modifiable C-terminal domain (CTD) that consists of variations of a consensus heptad repeat sequence (Y1S2P3T4S5P6S7). The consensus CTD repeat motif and tandem organization represent the ancestral state of eukaryotic RPB1, but across eukaryotes CTDs show considerable diversity in repeat organization and sequence content. These differences may reflect lineage-specific CTD functions mediated by protein interactions. Mammalian CTDs contain eight non-consensus repeats with a lysine in the seventh position (K7). Posttranslational acetylation of these sites was recently shown to be required for proper polymerase pausing and regulation of two growth factor-regulated genes.ResultsTo investigate the origins and function of RPB1 CTD acetylation (acRPB1), we computationally reconstructed the evolution of the CTD repeat sequence across eukaryotes and analyzed the evolution and function of genes dysregulated when acRPB1 is disrupted. Modeling the evolutionary dynamics of CTD repeat count and sequence content across diverse eukaryotes revealed an expansion of the CTD in the ancestors of Metazoa. The new CTD repeats introduced the potential for acRPB1 due to the appearance of distal repeats with lysine at position seven. This was followed by a further increase in the number of lysine-containing repeats in developmentally complex clades like Deuterostomia. Mouse genes enriched for acRPB1 occupancy at their promoters and genes with significant expression changes when acRPB1 is disrupted are enriched for several functions, such as growth factor response, gene regulation, cellular adhesion, and vascular development. Genes occupied and regulated by acRPB1 show significant enrichment for evolutionary origins in the early history of eukaryotes through early vertebrates.ConclusionsOur combined functional and evolutionary analyses show that RPB1 CTD acetylation was possible in the early history of animals, and that the K7 content of the CTD expanded in specific developmentally complex metazoan lineages. The functional analysis of genes regulated by acRPB1 highlight functions involved in the origin of and diversification of complex Metazoa. This suggests that acRPB1 may have played a role in the success of animals.

Project description:With a simple tandem iterated sequence, the carboxyl terminal domain (CTD) of eukaryotic RNA polymerase II (RNAP II) serves as the central coordinator of mRNA synthesis by harmonizing a diversity of sequential interactions with transcription and processing factors. Despite intense research interest, many key questions regarding functional and evolutionary constraints on the CTD remain unanswered; for example, what selects for the canonical heptad sequence, its tandem array across organismal diversity, and constant CTD length within given species and finally and how a sequence-identical, repetitive structure can orchestrate a diversity of simultaneous and sequential, stage-dependent interactions with both modifying enzymes and binding partners? Here we examine comparative sequence evolution of 58 RNAP II CTDs from diverse taxa representing all six major eukaryotic supergroups and employ integrated evolutionary genetic, biochemical, and biophysical analyses of the yeast CTD to further clarify how this repetitive sequence must be organized for optimal RNAP II function. We find that the CTD is composed of indivisible and independent functional units that span diheptapeptides and not only a flexible conformation around each unit but also an elastic overall structure is required. More remarkably, optimal CTD function always is achieved at approximately wild-type CTD length rather than number of functional units, regardless of the characteristics of the sequence present. Our combined observations lead us to advance an updated CTD working model, in which functional, and therefore, evolutionary constraints require a flexible CTD conformation determined by the CTD sequence and tandem register to accommodate the diversity of CTD-protein interactions and a specific CTD length rather than number of functional units to correctly order and organize global CTD-protein interactions. Patterns of conservation of these features across evolutionary diversity have important implications for comparative RNAP II function in eukaryotes and can more clearly direct specific research on CTD function in currently understudied organisms.

Dataset Information

Selective constraint and the evolution of the RNA polymerase II C-Terminal Domain.

Publications

Selective constraint and the evolution of the RNA polymerase II C-Terminal Domain.

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