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Zone in with Zon: RNA Is Present in Normal Genomic DNA and May Play Functional Role; Human Genomic DNA “Misincorporates” Over 1 Million Ribonucleotides Per Replication Cycle

In a stunning discussion in his most recent blog, posted on July 20, 2015, eminent nucleic acid chemist Jerry Zon, Ph.D., describes recent findings that a significant amount of RNA is present in normal DNA. In fact, Dr. Zon said that ribonucleotide "misincorporation" represents the most common type of replication error and occurs quite frequently in normal cells. Even more surprising, Dr. Zon said, there seem to be some positive consequences to having “some Rs among the Ds,” so to speak. Replication fidelity is, of course, hugely important and a key facet of replication fidelity, Dr. Zon noted, is the discrimination of the sugar backbone of the nucleic acid strand [ribose nucleic acid triphosphates (rNTPs) versus deoxyribose dNTPs] so that the correct sugar NTP is chosen. The two classes have very similar structures, differing by the added presence of only a single oxygen in the ribo versus deoxy forms. Hence, polymerases are challenged, Dr. Zon said, with distinguishing between the two types of nucleotides. Otherwise they risk inserting the incorrect substrate into the newly replicated nucleic acid strand. Consequently, sugar discrimination is a very important trait for DNA polymerases in this environment enriched for rNTPs over dNTPs. Recent studies of human polymerase delta found that in reactions containing nucleotide concentrations similar to those estimated to be present in mammalian cells, there was one rNTP incorporated per ∼2000 dNTPs—a result which predicts that human polymerase delta may introduce >1,000,000 rNMPs into the genome per replication cycle. Earlier results in analogous studies using yeast, led investigators to state that “[t]he idea that rNMP incorporation into DNA may be more common than previously appreciated leads one to wonder about possible benefits of rNMP incorporation," Dr. Zon reported.

The scientists then offered the following examples of beneficial effects of rNMP being incorporated into genomic DNA: mating type switching in haploid cells of the fission yeast Schizosaccharomyces pombe, which provides an example of ribonucleotide-based epigenetic imprint to differentiate sister chromatid strands; utilization of ribonucleotides during non-homologous end joining (NHEJ), which repairs double-strand breaks in DNA, via 3’-ribonucleotide stimulation of DNA ligase IV; and signaling for DNA mismatch repair (MMR) via rNTP incorporation during replication to mark the nascent strands for MMR.

In addition, Dr. Zon noted that four completely independent studies of methods for mapping genomic ribonucleotides were contemporaneously published on January 26, 2015.

Dr. Zon is a highly experienced and highly regarded nucleic acid chemist. He is currently Director of Business Development at TriLink BioTechnologies in San Diego, California. The entirety of Dr. Zon’s fascinating recent blog can be viewed at the link below. Previous Dr. Zon blogs can also be viewed at that site.

[Zone in with Zon blog post] [TriLink BioTechnologies]