Ribonucleotide errors, RNase HII, and ribonucleotide excision repair

Replicative DNA polymerases are responsible for the high-fidelity duplication of genomes in all organisms. The overall DNA replication process is highly accurate, with deoxyribonucleoside monophosphate (dNMP) errors occurring on the order of 1 in tens of millions of replicated bases. However, DNA polymerases are more prone to misincorporating ribonucleoside monophosphates (rNMPs) in place of their cognate dNMPs, with measurements on the order of 1 in a couple thousand base pairs synthesized. Owing in part to the high concentration of rNTPs relative to dNTPs in vivo, rNMPs may represent the most common nucleotide requiring removal from genomic DNA in organisms spanning all domains of life. Cells employ a set of pathways, including ribonucleotide excision repair (RER), to address abundant genomic rNMPs. Defects in ribonucleotide excision repair result in mutagenesis, neurological disorders, and embryonic lethality. In this review, we discuss the mechanisms for how ribonucleotides are misincorporated by DNA polymerases, how RNase H enzymes recognize and cleave RNA-DNA hybrids, and the process of ribonucleotide excision repair. Further, we review and discuss how ribonucleotide error correction occurs in eukarya, archaea, and bacteria, providing perspectives across a broad range of organisms and ribonucleotide resolution pathways.