Redundancy in ribonucleotide excision repair: Competition, compensation, and cooperation

Abstract

The survival of all living organisms is determined by their ability to reproduce, which in turn depends on accurate duplication of chromosomal DNA. In order to ensure the integrity of genome duplication, DNA polymerases are equipped with stringent mechanisms by which they select and insert correctly paired nucleotides with a deoxyribose sugar ring. However, this process is never 100% accurate. To fix occasional mistakes, cells have evolved highly sophisticated and often redundant mechanisms. A good example is mismatch repair (MMR), which corrects the majority of mispaired bases and which has been extensively studied for many years. On the contrary, pathways leading to the replacement of nucleotides with an incorrect sugar that is embedded in chromosomal DNA have only recently attracted significant attention. This review describes progress made during the last few years in understanding such pathways in both prokaryotes and eukaryotes. Genetic studies in Escherichia coli and Saccharomyces cerevisiae demonstrated that MMR has the capacity to replace errant ribonucleotides, but only when the base is mispaired. In contrast, the major evolutionarily conserved ribonucleotide repair pathway initiated by the ribonuclease activity of type 2 Rnase H has broad specificity. In yeast, this pathway also requires the concerted action of Fen1 and pol δ, while in bacteria it can be successfully completed by DNA polymerase I. Besides these main players, all organisms contain alternative enzymes able to accomplish the same tasks, although with differing efficiency and fidelity. Studies in bacteria have very recently demonstrated that isolated rNMPs can be removed from genomic DNA by error-free nucleotide excision repair (NER), while studies in yeast suggest the involvement of topoisomerase 1 in alternative mutagenic ribonucleotide processing. This review summarizes the most recent progress in understanding the ribonucleotide repair mechanisms in prokaryotes and eukaryotes.

Mechanism of Ribonucleotide Incorporation by Human DNA Polymerase η

“…2 The presence of ribonucleotides in DNA increases the possibility of spontaneous hydrolysis, causing DNA to break more frequently. These ribonucleotides are mainly removed from DNA by the RNase H2 pathway (1)(2)(3)(4)(5). DNA polymerases introduce ribonucleotides into DNA by misinserting them (6).…”

Analysis of Ribonucleotide Removal from DNA by Human Nucleotide Excision Repair

“…The high cellular level of ribonucleotides relative to deoxyribonucleotides and the lack of absolute selectivity of replicative DNA polymerases for dNTPs result in the incorporation of ribonucleotide monophosphates (rNMPs) 2 into genomic DNA (1)(2)(3). In mammals, this translates into the introduction of more than 1 million rNMPs into the genome during each cell cycle (4), suggesting that rNMPs can be considered the most prevalent form of endogenous DNA "damage."…”

The current state of eukaryotic DNA base damage and repair

“…RNase H1 (human: RNASEH1; S. cerevisiae : Rnh1) has recently been shown to also incise 3′ to the ribonucleotide, producing a single-nucleotide gap ( 79 ), leaving open the possibility of feeding into SN-BER for completion of repair. Advances in RER and other repair pathways for ribonucleotides have been reviewed in depth ( 80 ).…”