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The RNase H2 ribonuclease complex is a heterotrimeric endoribonuclease responsible for the major ribonuclease H activity in mammalian cells. In mouse, the complex is encoded by 3 genes located on chromosomes 8 (Rnaseh2a), 14 (Rnaseh2b) and 19 (Rnaseh2c). This enzyme specifically cleaves the 3’O-Phosphate bond of RNA in a DNA/RNA hybrids to produce 5’ phosphate and 3’hydroxyl ends.

Biological role

Ribonucleases H are the only known enzymes, able to degrade the RNA strand of a DNA/RNA hybrid in a sequence-nonspecific way. There are two types of RNase H (RNases H1 and RNases H2) classified according to their sequence conservation and substrate preference. Currently, three types of RNA/DNA hybrids are known: simple RNA/DNA duplexes (Figure 1A), RNA•DNA/DNA hybrids (Figure 1B), and DNA•RNAfew•DNA/DNA hybrids (Figure 1C). RNases H2 is totally able to cleave a single ribonucleotide embedded in a double strand DNA (DNA• RNAfew •DNA/DNA type) when RNases H1 require at least 4 ribonucleotides. This ability and their high expression in proliferating cells suggest that RNases H2 are involved in DNA repair and replication.

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Indeed, ribonucleotides are wrongly incorporated into DNA during DNA replication at a frequency of about 2 ribonucleotides per kb. With such frequency, these errors are by far the most abundant threat of DNA damaging. Hence, a correction is essential to the preservation of DNA integrity: the most common correction mechanism involves RNases H2 and is called Ribonucleotide Excision Repair (RER). The incorporation of ribonucleotides in DNA produce DNA•RNAfew•DNA/DNA hybrids from which the few misincorporated ribonucleotides can be removed by an RNase H2.

This repair activity is guided by the interaction between C-terminus of RNase H2B protein and the DNA clamp PCNA. This interaction occurs through a hydrophobic conserved peptide motif called the PCNA interaction peptide PIP (PIP-box: Residues 294 to 301 MKSIDTFF of H2B protein) that interacts with a hydrophobic groove near the PCNA C-terminus. This interaction allows RNase H2 to scan DNA for misincorporated ribonucleotides which makes the Ribonucleotide Excision Repair more efficient.

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Structural highlights

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