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| Symbol |
RNASEH2A |
| Full Name |
Ribonuclease H2 Subunit A |
| Chromosome |
19q13.13 |
| NCBI Gene |
10535 |
| Ensembl |
ENSG00000135838 |
| OMIM |
610225 |
| UniProt |
Q9UHQ2 |
| Diseases |
[Aicardi-Goutières Syndrome](/diseases/aicardi-goutieres-syndrome), [Aicardi-Goutières Syndrome](/diseases/aji) |
| Expression |
Ubiquitously expressed; high expression in brain, heart, skeletal muscle |
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].
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.
- Chromosome: 19q13.13
- Location: chr19: 38877012-38883617
- Strand: Plus strand
- Exons: 8
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
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
- 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
- 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 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
- Missense mutations typically cause milder disease
- Null/truncating mutations cause severe early-onset AGS
- Some variants may have incomplete penetrance
Recent studies suggest RNASEH2A variants may increase cancer risk:
- Increased incidence of lymphoproliferative disorders
- Potential role in genome instability-driven tumorigenesis
RNASEH2A is ubiquitously expressed with highest levels in:
- Brain (neurons and glia)
- Heart
- Skeletal muscle
- Liver
- Kidney
- Primarily nuclear localization
- Associates with chromatin
- Enriched in nucleolus during certain cell cycle phases
RNASEH2A expression is regulated by:
- Cell cycle (peaks in S phase)
- DNA damage responses
- Interferon signaling (in some contexts)
Strategies
- J### TreatmentAK inhibitors: Suppress interferon signature in AGS
- Antimetabolite therapy: Reversing ribonucleotide incorporation
- Gene therapy: Restoring RNase H2 function
- Understanding the molecular mechanisms of AGS pathogenesis
- Developing small molecule RNase H2 activators
- Exploring interferon-targeted therapies
- Mutations in RNASEH2A cause Aicardi-Goutières syndrome. American Journal of Human Genetics, 2008.
- RNase H2 mutations: expanding the AGS phenotype. Brain, 2009.
- The RNase H2 complex: structure and function. Journal of Biological Chemistry, 2019.
- Ribonucleotide excision by RNase H2. Journal of Biological Chemistry, 2014.