The Balancing Act of Ribonucleotides in DNA

The abundance of ribonucleotides in DNA remained undetected until recently because they are efficiently removed by the ribonucleotide excision repair (RER) pathway, a process similar to Okazaki fragment (OF) processing after incision by Ribonuclease H2 (RNase H2). All DNA polymerases incorporate ribonucleotides during DNA synthesis. How many, when, and why they are incorporated has been the focus of intense work during recent years by many labs. In this review, we discuss recent advances in ribonucleotide incorporation by eukaryotic DNA polymerases that suggest an evolutionarily conserved role for ribonucleotides in DNA. We also review the data that indicate that removal of ribonucleotides has an important role in maintaining genome stability.

TrendsRibonucleotides are incorporated in DNA during DNA synthesis and are removed by the ribonucleotide excision repair pathway, which is initiated by RNase H2.Ribonucleotides are markers for the newly synthesized DNA strand and strand-discrimination signals for the mismatch repair system.Recently, ribonucleotide mapping in DNA enabled mapping of replication origins and showed that Pol α substantially contributes to genomic DNA after OF maturation.In the absence of RNase H2, topoisomerase 1 (Top1) can initiate the removal of ribonucleotides in DNA in error-free or error-prone processes.Deleting RNase H2 causes high levels of ribonucleoside monophosphates (rNMPs) in DNA, which is tolerated in yeast but causes embryonic death in mice. Biallelic mutations in RNase H2 in humans cause a neuroinflammatory autoimmune disease, Aicardi–Goutières Syndrome, possibly due to the accumulation of cytosolic nucleic acids.