Origins of Life and Evolution of the Biosphere (2005) 36: 413–420 DOI: 10.1007/s11084-005-9006-1

c Springer 2005 

INTRAMOLECULAR RNA REPLICASE: POSSIBLY THE FIRST SELF-REPLICATING MOLECULE IN THE RNA WORLD WENTAO MA1,2,∗ and CHUNWU YU3 1 College

of Life Sciences, Wuhan University, Wuhan 430072, P.R.China; 2 State Key Laboratory of Software Engineering, Wuhan University, Wuhan 430072, P.R.China; 3 College of Computer Sciences, Wuhan University, Wuhan 430072, P.R.China (∗ author for correspondence, e-mail: [email protected])

(Received 19 August 2005; accepted in revised form 17 November 2005)

Abstract. Although there is more and more evidence suggested the existence of an RNA World during the origin of life, the scenario concerning the origin of the RNA World remains blurry. Usually it is speculated that it originated from a prebiotic nucleotide pool, during which a self-replicating RNA synthesis ribozyme may have emerged as the first ribozyme – the RNA replicase. However, there is yet no persuasive supposition for the mechanism for the self-favouring feature of the replicase, thus the speculation remains unconvincing. Here we suggest that intramolecular catalysis is a possible solution. Two RNA synthesis ribozymes may be integrated into one RNA molecule, as two functional domains which could catalyze the copy of each other. Thus the RNA molecule could self-replicate and be referred to as “intramolecular replicase” here. Computational simulation to get insight into the dynamic mechanism of emergence of the intramolecular replicase from a nucleotide pool is valuable and would be included in a following work of our group. Keywords: intramolecular catalysis, molecular evolution, origin of life, RNA replicase, RNA World

1. Considering the Origin of the RNA World The RNA World hypothesis, with a core idea that there was once an RNA World preceding our contemporary DNA /RNA /protein life World, has become more and more popular in the field of origin of life (Joyce, 2002; Orgel, 2004). Thus the problem of origin of the RNA World has attracted more and more attention. A relatively direct consideration is that, the RNA World originated de novo from non-life world (Joyce and Orgel, 1999), which involves prebiotic synthesis of nucleotides, prebiotic formation of polynucleotides from the nucleotides, and emergence of various ribozymes. 2. An RNA Synthesis Ribozyme Should Emerge First Though prebiotic synthesis of nucleotides has not been demonstrated, a number of achievements have been achieved on this aspect (Miller, 1998; Schwartz, 1998; Orgel, 2004). Mineral catalysis has been suggested to be involved in the prebiotic

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formation of polynucleotides (Ferris et al., 1996; Ferris, 2002; Ertem, 2004). Now let us focus on a following stage, the emergence of ribozymes. Through random (mineral-catalytic) ligation in a possible prebiotic nucleotide pool, RNA molecules with various sequences may appear. Some of these molecules may have characteristic sequences and act as ribozymes. However, if a ribozyme molecule could not replicate and grow into a population in the system, the ribozyme as a ‘breed’ would disappear again when the molecule degrades. Nonenzymatic template-directed synthesis (Orgel, 1992; Rohatgi et al., 1996; Kozlov and Orgel, 2000) provides a basic mechanism for the replication of RNA molecules. However, the low efficiency of the mechanism is not likely to support even one turn of replication of a ribozyme before it degrade. Therefore, a sort of ribozymes catalyzing the synthesis of RNA should emerge first to improve the efficiency of the replication mechanism before any other functional ribozymes could emerge in the system. We use the word ‘emerge’ to express the meaning ‘appear and spread (grow into a population)’ here.

3. The RNA Synthesis Ribozyme Should be Self-Favouring – ‘The Replicase’ Now we suppose that a molecule of the RNA synthesis ribozyme appears via mineral-catalytic ligation from a nucleotide pool. If it could catalyze replication of all the RNA molecules in the system at similar efficiency, the ribozyme itself would not grow into population via replication, because it has not any superiority in the competition for limited ‘nutrients’ (substrates for synthesis) among large numbers of differing RNA molecules in the system. Finally the RNA synthesis ribozyme would disappear all the same accompanying the degradation of the molecule. Therefore, there should be a mechanism to ensure the RNA synthesis ribozyme to favour the replication of its own breed. In this context, the ribozyme could be referred as a ‘replicase’ (Joyce and Orgel, 1999). However, the mechanism for the self-favour is still a puzzle. A simple idea is that there is a special tag sequence in the molecule of the replicase (and also its complement), and the ribozyme could bind to its target via the recognition of the tag (Wein and Maizels, 1987). However, among large numbers of randomly forming RNA molecules in the system, there are many other RNA molecules also including the tag. Theoretically, the ratio of tag-included sequences to tag-included RNA synthesis ribozymes is just the same with the ratio of random sequences to RNA synthesis ribozymes, thus no self-favour is available yet. Spacial limitation may be a possible mechanism. There has been computer simulation research revealing that replicators (a simplified model for replicases) with limited dispersal may evolve towards higher efficiency and fidelity (Szabo et al., 2002; Scheuring et al., 2003). However, up to now no research has shown such partial spacial limitation effective enough to favour the emergence of such replicators from the background of random sequence formation. Complete spacial limitation through membrane compartmentation is likely to be a final solution, inspired by the contemporary cellular life.

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However, the emergence of the RNA synthesis ribozyme together with the emergence of membrane, which may involve some other ribozyme, such as the ribozyme catalyzing synthesis of subunits of the membrane (Szostak et al., 2001), seems a complicated mechanism and much less possible, if not impossible.

4. Intramolecular Catalysis: A Possible Solution for Self-Favour Up to now, almost all attention has been paid to the mechanism of intermolecular catalysis, with which a RNA synthesis ribozyme molecule may catalyze the replication of other molecules of its own breed (including the complement of the ribozyme) (Bartel, 1999; Johnston et al., 2001; McGinness and Joyce, 2002; McGinness and Joyce, 2003). while the possibility of self-replication of a replicase through intramolecular catalysis is nearly neglected, except a little associated work involving self-replication of an RNA ligase ribozyme with pre-supplied two or several special building blocks of the same molecule (Paul and Joyce, 2002; Kim and Joyce, 2004). Actually, if two (or more) RNA synthesis ribozymes ‘exist as domains’ in one molecule, self-favour is out of question. Suppose that there are two such domains in a molecule, through intramolecular catalysis (Bartel and Szostak, 1993; Jaeger et al., 1999; Fedor, 2000) the domains may favour the copying of each others, resulting in replication of the whole molecule (Figure 1). Thus the molecule could be referred to as an ‘intramolecular replicase’, an RNA catalyzing replication of its own molecule, instead of the usually referred ‘intermolecular replicase”, the RNA catalyzing replication of other molecules of its own breed.

5. The Intramolecular Replicase is Likely to Emerge First Theoretically, the possibility of appearance of a characteristic sequence via random chemical ligations descends exponentially accompanying the increase of the sequence’s length. In principle, comparing with the intramolecular catalysis, the intermolecular catalysis requires an additional domain for the binding of target template-substrate complexes, thus less likely to appear first. In fact, engineering efforts based on intramolecular RNA synthesis ribozyme to favour intermolecular catalysis have been through the introduction of additional chain length (Johnston et al., 2001). It has long been known that intramolecular RNA ligation may be realized in rather simple RNA molecules, such as the hairpin ribozyme (Fedor, 2000) and the hammerhead ribozyme (Hammann and Lilley, 2002). If the ligase activity could be extended to a degree to catalyze the ligation of either monomers or oligomers attracted and aligned adjacently on the template part of the same molecule in a considerable range (Figure 1B), that would render a primordial intramolecular replicase possible.

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Figure 1. Molecular self-replication based on intramolecular catalysis. (A), Intramolecular RNA synthesis ribozymes. Rectangles represent active domains of the ribozymes. (B), Catalytic ranges (labelled with arrows) of an active domain. (C), An RNA molecule contain two active domains whose catalytic ranges cover the whole molecule thus the whole molecule could be copied. The upper labelled range is the upstream catalytic range of the second domain, and the lower labelled range is the downstream catalytic range of the first domain. (D), Two possible replicating mechanisms for intramolecular replicases. The upper one requires that the active domain is palindromic thus the copying of the molecule results in replication. The lower one does not require a palindromic domain, supposing that the active domain in the partially synthesized chain could fold back to catalyze supervenient synthesis of the left part. Grey rectangles represent complementary sequences of the active domains.

Additionally, the first turn replication of an intermolecular replicase requires ‘a chance encounter’ of two appearing replicase molecules (or a replicase molecule and a complement of replicase molecule) before degradation of either one, thus reducing the emerging possibility even more. There is no similar ‘awkwardness’ for the emergence of intramolecular replicases.

6. The Hypothesis of Intramolecular Replicase Here we could imagine a possible scenario which may have happened in the prebiotic environments (Figure 2). In a prebiotic pool, nucleotides formed from raw materials. They could join together and form polynucleotides under mineral catalysis. The polynucleotides could template-direct the formation of their complementary

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Figure 2. A scheme describing the hypothesis of intramolecular replicase. Newly emerging events are drawn in black in the center of the subfigures while old events in grey aside. (A), Formation of nucleotides (L-shaped) from raw materials (dots). (B), Mineral-catalytic ligation. (C), Nonenzymatic template-directed ligation. (D), Appearance of intramolecular ligases. (E), Emergence of intramolecular replicases.

chain. Sequences with a short special domain catalyzing the template-directed ligation intramolecularly, i.e. intramolecular RNA ligases, appear. Then sequences containing two of such special domains in a suitable distance (refer to Figure 1B), i.e. intramolecular RNA replicases, appear and spread via replication through intramolecular catalysis (refer to Figure 1D). Such intramolecular replicases are very likely to have been the first functional RNA molecules which might have emerged from prebiotic nucleotide pools. How the system including intramolecular replicases could further evolve to the real RNA World is a question that should be answered in the hypothesis of intramolecular replicase. Some other functional domains may emerge subsequently in the replicase sequence, for instance, a domain with activity of excising other RNA molecules, since the achieving of additional ‘nutrient’ is very important to compete against other ‘species’. A functional domain may appear via addition mutation at the ends of a replicase molecule and be also covered in the catalytic range of ligase domains in the replicase molecule, and thus could also be copied during the replication of the molecule. If the advantage brought by the functional domain could overcome the disadvantage of additional length brought by it, replicases contained the domain may spread in the system.

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No matter how, the most important event after the emergence of intramolecular replicases may be the emergence of a functional domain favouring formation of a membrane, probably through catalyzing synthesis of subunits of the membrane (Szostak et al., 2001; Ono, 2005). Membranes forming around replicases may provide advantage of accumulating raw materials for synthesizing nucleotides (Sacerdote and Szostak, 2005) or protecting the replicase from degradation, thus favouring the spread of the replicases containing such a domain. The emergence of membrane provides an efficient self-favour mechanism for intermolecular catalysis. The realization of different catalytic functions in distinct molecules brings greater efficiency to the ‘species’. Intermolecular RNA synthesis ribozymes may emerge in this stage, which labelled the separation of catalytic function and genetic function (the former intramolecular replicase would lose its value as ribozyme and become primordial genome gradually). Thereafter, more complicated functions requiring more catalytic steps, such as the catalytic synthesis of nucleotides, could be realized on independent special ribozyme molecules (Joyce, 2002). This labelled the emergence of metabolism, and would finally bring more complex ‘species’ into reality and lead to the prosperity of the RNA World.

7. Working on The Hypothesis of Intramolecular Replicase Experimental studies on the origin of the RNA World are still facing a lot of obstacles due to the shortage of our knowledge in prebiotic chemistry (Joyce, 2002; Orgel, 2004). Though demonstrating in laboratory the scenario of the above mentioned hypothesis of intramolecular replicase seems not quite possible in the near future, construction of an intramolecular replicase via in vitro molecular evolution engineering (Bartel and Szostak, 1993; Joyce, 2004) is a promising direction on the way. Traditional theoretical researches in the field (Monteiro and Piqueira, 1998; Monteiro and Piqueira, 1999; Wattis and Coveney, 1999), usually in terms of standard chemical kinetic formalism, are often not powerful enough to get insight into the detailed mechanisms of the complex systems involved. On the other hand, computer simulation provides an excellent “virtual” platform for studying the complex systems ((Szabo et al., 2002; Scheuring et al., 2003; Ono, 2005; Taylor, 2005). Its main shortcoming lies in the inevitable introduction of assumptions for simplification in its model, thus its result needs further validating by laboratory work. Nevertheless, it may provide valuable clues for experimental designs and help to illustrate the underlying mechanisms whether experimental results have been achieved yet or not. To study the plausibility of the scenario described in the hypothesis of intramolecular replicase and the dynamics involved, we are constructing a computer simulation on the chemical evolution in a nucleotide pool, which is expected to be reported in the near future.

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Acknowledgements Financial support by National Natural Science Foundation of China, Hubei Natural Science Foundation and State Key Laboratory of Software Engineering in Wuhan University is gratefully acknowledged.

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