Causes and consequences of ribonucleotide incorporation into nuclear DNA

Intuitively one would not expect that ribonucleotides are incorporated into nuclear DNA beyond their role in priming Okazaki fragments, nor that such incorporation would be functional. However, several recent studies have shown that not only are ribonucleotides present in the nuclear DNA, but that they can be incorporated by at least two different mechanisms: random ‘mis’-incorporation of ribonucleotides, which occurs at a surprisingly high frequency; and site-specific incorporation at a stalled fork. Importantly, in the latter case, the ribonucleotides have been shown to have a biological function – acting to initiate a replication-coupled recombination event mediating a cell type change. Traditionally, it has been thought that ‘random’ ribonucleotide incorporation causes genetic instability, but new evidence suggests there may be a fine balance between mechanisms preventing and incorporating ribonucleotides into genomic DNA. Indeed, genomic ribonucleotides might have diverse roles affecting genetic stability, DNA damage repair, heterochromatin formation, cellular differentiation, and development.