RNASEH2A (Ribonuclease H2 Subunit A) is a gene located on chromosome 19q13.13 that encodes the catalytic subunit of the RNase H2 complex. This enzyme plays a critical role in removing RNA from DNA-RNA hybrids and processing ribonucleotides incorporated into genomic DNA. RNASEH2A is essential for maintaining genome integrity, and mutations cause Aicardi-Goutières syndrome (AGS), a severe neurodevelopmental disorder [1][2].
Gene Structure
The RNASEH2A gene spans approximately 6.5 kb and consists of 8 exons. The gene encodes a 299-amino acid protein that forms the catalytic core of the RNase H2 complex.
Genomic Organization
Chromosome: 19q13.13
Location: chr19: 38877012-38883617
Strand: Plus strand
Exons: 8
The RNase H2 Complex
RNase H2 is a heterotrimeric complex consisting of:
RNASEH2A (catalytic subunit): Contains the active site for ribonuclease H activity
RNASEH2B (non-catalytic subunit): Supports complex stability and localization
RNASEH2C (non-catalytic subunit): Assists in complex assembly
The complex is also known as RNase H2 and is distinct from RNase H1, which is a monomeric enzyme.
Protein Structure and Function
Domain Architecture
RNASEH2A contains:
N-terminal region: Involved in complex formation with RNASEH2B and RNASEH2C
RNase H-like domain: Contains the catalytic center for ribonuclease activity
C-terminal tail: Important for protein-protein interactions
Catalytic Activity
RNase H2 specifically cleaves RNA within DNA-RNA hybrids:
Prefers substrates with single embedded ribonucleotides
Cleaves the phosphodiester bond 5' to the ribonucleotide
Requires divalent metal ions (Mg²⁺ or Mn²⁺) for catalysis
Can process multiple ribonucleotides in a row
Biological Functions
DNA Repair
Ribonucleotide removal: RNase H2 is the primary enzyme for removing misincorporated ribonucleotides from DNA
Genome stability: Prevents accumulation of ribonucleotides in genomic DNA
DNA replication fidelity: Ensures removal of RNA primers during DNA synthesis
RNA Processing
R-loop resolution: Processes RNA-DNA hybrids that form during transcription
Telomere maintenance: Involved in processing RNA components of telomeres
Maturation of RNA primers: Processes RNA primers in various cellular processes
RNASEH2A in Disease
Aicardi-Goutières Syndrome (AGS)
RNASEH2A mutations account for approximately 10-15% of AGS cases. The disease is characterized by:
Progressive encephalopathy
Microcephaly
Intracranial calcifications
Leukodystrophy
Elevated type I interferon signature
Early-onset severe neurological impairment
Pathogenic variants in RNASEH2A include:
Missense mutations (e.g., R108W, Y113C, G118D)
Nonsense and frameshift mutations
Splice-site mutations
Genotype-Phenotype Correlations
Missense mutations typically cause milder disease
Null/truncating mutations cause severe early-onset AGS
Some variants may have incomplete penetrance
Cancer Predisposition
Recent studies suggest RNASEH2A variants may increase cancer risk:
Increased incidence of lymphoproliferative disorders
Potential role in genome instability-driven tumorigenesis
Expression Pattern
Tissue Distribution
RNASEH2A is ubiquitously expressed with highest levels in:
Brain ([neurons](/entities/neurons) and glia)
Heart
Skeletal muscle
Liver
Kidney
Cellular Localization
Primarily nuclear localization
Associates with chromatin
Enriched in nucleolus during certain cell cycle phases
Regulation
RNASEH2A expression is regulated by:
Cell cycle (peaks in S phase)
DNA damage responses
Interferon signaling (in some contexts)
Therapeutic Implications
Strategies
J### TreatmentAK inhibitors: Suppress interferon signature in AGS
[DNA Damage and Repair in Neurodegeneration](/mechanisms/dna-damage-repair)
[Genes Index](/genes)
[Proteins Index](/proteins)
References
[Crow YJ, Leitch A, Hayward BE, et al, "Mutations in RNASEH2A cause Aicardi-Goutières syndrome." American Journal of Human Genetics (2008)](https://doi.org/10.1016/j.ajhg.2008.01.007)
[Rice GI, Kasher PR, Forte GM, et al, "Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia." Brain (2014)](https://doi.org/10.1093/brain/awu114)
[Reijns MA, Bubeck D, Gibson LC, et al, "The structure of the human RNase H2 complex defines the molecular basis for Aicardi-Goutières syndrome." Nature Structural & Molecular Biology (2011)](https://doi.org/10.1038/nsmb.2093)
[Chon H, Vassilev A, DePamphilis ML, et al, "Contributions of the two accessory subunits, RNASEH2B and RNASEH2C, to the activity and properties of human RNase H2 complex." DNA Repair (2009)](https://doi.org/10.1016/j.dnarep.2008.09.005)
[Hiller B, Achleitner M, Glage S, et al, "Mammalian RNase H2 can substitute for the removal of embedded ribonucleotides during DNA replication." Nucleic Acids Research (2012)](https://doi.org/10.1093/nar/gks030)