Ribonucleotides in DNA: Origins, repair and consequences

Abstract

While primordial life is thought to have been RNA-based (Cech, Cold Spring Harbor Perspect. Biol. 4 (2012) a006742), all living organisms store genetic information in DNA, which is chemically more stable. Distinctions between the RNA and DNA worlds and our views of “DNA” synthesis continue to evolve as new details emerge on the incorporation, repair and biological effects of ribonucleotides in DNA genomes of organisms from bacteria through humans.

7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action

“…HPLC-MS analysis of DNA lysates revealed that AB61 is incorporated into DNA predominantly as a ribonucleotide and only rarely as a 2 0 -deoxyribonucleotide (30:1 ratio) which means that AB61-TP is a substrate for human DNA polymerases. Despite this finding might seem surprising, ribonucleotide incorporation into cellular DNA is quite common (40)(41)(42). In contrast, tubercidin (2) and toyocamycin (3) are incorporated into DNA only after reduction by ribonucleotide reductase as 2 0 -deoxyribonucleotides.…”

Topoisomerase I Alone Is Sufficient to Produce Short DNA Deletions and Can Also Reverse Nicks at Ribonucleotide Sites

“…The events following the formation of Top1-induced nicks that eventually result in DNA deletions at short repeat sites have been the subject of much speculation (8,9,18,25). Here, we provide experimental evidence for a sequential model (25).…”

“…5, inset) (16,24). The subsequent events leading to DNA deletions at short repeat sites have been the subject of much speculation (8,9,16,18,25). Here, we demonstrate that Top1 alone is sufficient to induce the observed DNA deletion at a short repeat site via sequential cleavage of DNA adjacent to the rNMP site.…”

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

“…It has been studied how the additional presence of a reactive 2′-hydroxyl group on the sugar ring may: i) alter the DNA physical properties, reducing its elasticity [102,103] and structure in a sequence dependent manner [104][105][106][107][108]; ii) induce DNA replication or transcription arrest making the DNA backbone prone to hydrolysis triggering a persistent genomic instability [103,108,109]. This incorporation occurs quite frequently into the cell [110,111], potentially during every DNA replication reaction [110]. It has been estimated that a few thousands of rNMPs are embedded in budding yeast genome [110] and over a million in mouse genome [112].…”

“…It has been estimated that a few thousands of rNMPs are embedded in budding yeast genome [110] and over a million in mouse genome [112]. The higher amount of the cellular pool of ribonucleotides (rNTPs), compared to their corresponding deoxyribonucleotides (dNTPs) [110] counterparts, combined to an incomplete elimination of RNA primers used in the generation of Okazaki fragments [113] and an imprecise 3′-exonucleolytic proofreading activity of replicative DNA polymerases [113][114][115][116][117] are some of the major causes of the rNMPs incorporation into genomic DNA. Moreover, another potential significant, yet poorly characterized, source of rNMPs incorporated in DNA is oxidative stress.…”