RNAP laboratory develops novel theory on evolution of transcription
27 January 2011
Finn Werner and Dina Grohmann from the RNAP laboratory at UCL SMB have developed a novel theory on the evolution of transcription regulation – the ‘elongation first hypothesis’ 1. By studying the structure and function of the engine of transcription, RNA polymerase (RNAP), and the factors that orchestrate its activities they conclude that the ancestral RNAP of the last universal common ancestor (LUCA) of all extant life was regulated during the elongation phase of the transcription cycle. This theory represents a paradigm shift in the field since according to textbook dogma RNAP - and thereby gene expression - is principally controlled at the level of transcription initiation.
All organisms alive today belong to one of the three ‘domains of life’ Bacteria, Archaea and Eukarya, and all are descendants from a hypothetical common ancestral life form, the LUCA. This kinship is reflected in the molecular architecture of RNAPs, which read the genetic information by transcribing DNA into RNA, and thereby act as ‘gatekeepers of the genome’. The activity of RNAP is controlled by transcription factors that are specific for the three phases of the transcription cycle: initiation, elongation and termination.
The RNAP laboratory has recently carried out a functional and crystallographic analysis of the universally conserved elongation factor Spt4/5 2. A careful scrutiny of its properties revealed an astonishing degree of similarity between its homologues across all three domains. This is in stark contrast to the factors that facilitate transcription initiation, which are not evolutionary conserved. In bacteria a family of proteins called s factors is strictly required for initiation, whereas in Archaea and Eukarya the evolutionary unrelated TBP and TFIIB factors facilitate initiation. Werner and Grohmann were puzzled by the contrasting phylogeny of initiation and elongation factors, since the RNAP itself is highly conserved in the three domains. According to the law of parsimony (‘Occam’s razor’) it is most likely that the initiation factors emerged independently in the bacterial and archaeo-eukaryotic lineages of life - after LUCA and not before the split into separate domains.
In summary, the ‘elongation first hypothesis’ states that (i) LUCA utilised neither s- nor TBP/TFIIB-like factors and initiated transcription in a factor-independent fashion, and (ii) LUCA’s RNAP was regulated by an ancestral form of Spt5 during the elongation phase of transcription. This implies that the regulation of elongation predates the regulation of initiation in evolution. The theory will be published in the journal Nature Reviews Microbiology in February 20111.
Commenting on the research, Dr Finn Werner said: 'Transcription lies at the very heart of every major biological process that involves our genes. Elucidating its structure and function is an essential knowledge base. Exploring its evolution is to extrapolate back in time towards nothing less than the origin of information processing in biology, to the Origin of Life'.
1 ‘Evolution of RNA polymerase in the three domains of life’, Finn Werner and Dina Grohmann, Nature Reviews Microbiology 2010 Feb
2 ‘Spt4/5 stimulates transcription elongation through the RNA polymerase clamp coiled-coil motif’. Hirtreiter A, Damsma GE, Cheung AC, Klose D, Grohmann D, Vojnic E, Martin AC, Cramer P, Werner F. Nucleic Acids Research, 2010 Jul 1;38(12):4040-51