RNA and Metals as a Window onto Ancient Biochemistry

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Guth-Metzler, Rebecca
Williams, Loren D.
Glass, Jennifer B.
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RNA is one of life’s three essential biopolymers. RNA is so entrenched in biology that it is thought to have arisen near the origin of life itself. Work herein uses RNA’s ancient relationship with divalent metals (M²⁺) as a detective’s lens to peer back into time. RNA uses Mg²⁺ as its primary M²⁺ partner in modern life. However, RNA evolved when Fe²⁺ was more available, in a time before rising atmospheric oxygen caused Fe²⁺ to “rust out”. Moreover, Fe²⁺ exposed to oxygen forms free radicals that break down biomolecules including RNA. Our research shows that Fe²⁺ kept in anoxic conditions mimicking early Earth does not cause oxidation reactions, instead having the same reaction with RNA as does Mg²⁺. Reaction similarity of Fe²⁺ and Mg²⁺ adds to growing evidence that Fe²⁺ may have been an early binding partner of RNA, and that RNA adaption through swapping out M²⁺ to support RNA survival over billions of years. Moreover, Fe²⁺ may have accelerated early RNA evolution, allowing RNA to diversify and multiply. Yet, to RNA, M²⁺ is a double-edged sword. While M²⁺ ions catalyze RNA cleavage, shortening its lifetime, they also promote RNA folding, which in turn protects RNA from cleavage. We further combine these concepts into the following scheme: too little M²⁺ shortens RNA lifetime because there is no folding and therefore no cleavage protection, too much M²⁺ shortens RNA lifetime because cleavage overwhelms folding protection, but the in-between “Goldilocks peak” of moderate [M²⁺] is “just right”. We find RNA Goldilocks peaks that take on a variety of appearances, revealing unexpected complexity from the innate RNA-Mg²⁺ relationship. The average Goldilocks peak of modern RNA may reflect the metal conditions of its origin, giving a clearer picture of the environment where life emerged. The Goldilocks peak boost to RNA lifetime perhaps caused RNA to win out over competing polymers on early Earth, a possible explanation for why RNA is one of life’s universal biopolymers.
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