Affinage

RNASEH2A

Ribonuclease H2 subunit A · UniProt O75792

Length
299 aa
Mass
33.4 kDa
Annotated
2026-06-10
15 papers in source corpus 9 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNASEH2A encodes the catalytic subunit of the heterotrimeric RNase H2 complex, which cleaves RNA in RNA:DNA hybrids and removes ribonucleotides misincorporated into genomic DNA, thereby safeguarding genome stability (PMID:23592335, PMID:39217460). Within the complex it assembles with RNASEH2B and RNASEH2C, and its catalytic function is separable from complex assembly: truncating mutations can permit heterotrimer formation while abolishing enzymatic activity (PMID:23592335). In humans, synonymous variants that create cryptic splice donor sites in exon 1 reduce functional enzyme and cause Aicardi-Goutières syndrome, with residual activity dependent on leaky splicing of full-length protein (PMID:23592335). Loss of RNase H2 activity in vivo causes ribonucleotide accumulation in DNA, DNA fragmentation, and innate immune/inflammatory activation, establishing the link between defective ribonucleotide removal and interferon-associated pathology (PMID:39217460); patient-derived cells additionally show mitochondrial damage and metabolic dysfunction that may feed inflammatory signaling (PMID:36430958). Beyond its housekeeping role, RNASEH2A is transcriptionally upregulated by SP1 in hepatocellular carcinoma and by ELK3 in glioma, and is induced by HPV E7 through an E2F1-dependent axis; in these contexts it promotes proliferation, cell cycle progression, anchorage-independent growth, EMT, and therapy resistance (PMID:19139135, PMID:27176716, PMID:30696738, PMID:37520960, PMID:36638810).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 Medium

    Established that RNASEH2A has a cancer-cell-selective functional requirement, raising it as a potential oncology target rather than a purely housekeeping gene.

    Evidence siRNA knockdown with soft-agar anchorage-independent growth versus proliferation assays in cancer lines and normal cells

    PMID:19139135

    Open questions at the time
    • Did not connect anchorage-independent growth to the enzyme's catalytic ribonucleotide-removal activity
    • Mechanism of cancer-cell selectivity unresolved
  2. 2013 High

    Defined RNASEH2A as the catalytic subunit of RNase H2 and showed catalysis is genetically separable from heterotrimer assembly, explaining how disease mutations disable function without disrupting the complex.

    Evidence Splicing/RT-PCR analysis, in vitro catalytic activity assays, and complex assembly assays on patient variants

    PMID:23592335

    Open questions at the time
    • Structural basis of catalysis not resolved here
    • Quantitative relationship between residual activity and disease severity not defined
  3. 2016 Medium

    Extended the cancer phenotype to glioblastoma, linking RNASEH2A to cell cycle progression and survival in vitro and in vivo.

    Evidence shRNA knockdown with cell cycle/apoptosis flow cytometry, colony formation, xenograft, and microarray (IL-6, FAS pathways)

    PMID:27176716

    Open questions at the time
    • IL-6/FAS pathway link is correlative from microarray, not mechanistically dissected
    • Catalytic dependence of the phenotype not tested
  4. 2019 Medium

    Identified a viral oncoprotein input to RNASEH2A expression, defining the E7→E2F1→RNASEH2A transcriptional axis in keratinocytes.

    Evidence HPV E7 expression with E2F1 knockdown/rescue and gene expression analysis in human keratinocytes

    PMID:30696738

    Open questions at the time
    • Direct E2F1 binding to the RNASEH2A promoter not shown
    • Functional consequence of induced RNASEH2A in HPV biology not established
  5. 2021 Low

    Suggested a cell-cycle-associated interactome for RNASEH2A beyond RNA:DNA hybrid processing.

    Evidence Mass spectrometry of RNASEH2A-bound proteins with co-expression bioinformatics

    PMID:33805806

    Open questions at the time
    • Single pulldown/MS without reciprocal Co-IP or biochemical validation of individual interactors
    • No functional test of any identified interaction
  6. 2022 Medium

    Connected RNASEH2A loss to mitochondrial damage and metabolic dysfunction as a candidate contributor to AGS inflammation.

    Evidence TEM, membrane potential/ROS flow cytometry, Seahorse metabolic analysis, immunofluorescence, and qPCR in patient-derived LCLs

    PMID:36430958

    Open questions at the time
    • No rescue experiment to show mitochondrial defects are causally downstream of RNASEH2A loss
    • Causal link from mitochondrial damage to interferon activation not demonstrated
  7. 2023 Medium

    Defined two direct transcriptional activators (SP1 in HCC, ELK3 in glioma) that drive RNASEH2A-dependent malignant phenotypes including EMT and oxaliplatin resistance.

    Evidence Dual-luciferase reporter and ChIP for promoter binding, knockdown with overexpression rescue, and proliferation/migration/sphere assays

    PMID:36638810 PMID:37520960

    Open questions at the time
    • Whether the pro-tumor effects depend on enzymatic activity is untested
    • Single-lab findings per tumor context
  8. 2024 High

    Demonstrated in vivo that RNASEH2A is essential for genome stability and that its loss triggers ribonucleotide accumulation, DNA fragmentation (ribodysgenesis), and innate immune activation.

    Evidence Zebrafish rnaseh2a knockout with rNMP incorporation assays, inflammatory marker quantification, and generational viability crosses

    PMID:39217460

    Open questions at the time
    • Identity of the innate immune sensor driving inflammation not pinned down
    • Tissue-specific vulnerability (brain, testes) mechanism unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the cancer-promoting and therapy-resistance functions of RNASEH2A require its ribonucleotide-removal catalytic activity, and how genomic ribonucleotide accumulation is mechanistically transduced into interferon signaling, remain unresolved.
  • No catalytic-dead rescue tying tumor phenotypes to enzymatic function
  • Sensor and signaling route from rNMP accumulation to innate immunity undefined
  • Structural model of the human catalytic subunit absent from the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005739 mitochondrion 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 1
Partners
E2F1ELK3RNASEH2BRNASEH2CSP1
Complex memberships
RNase H2

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Two synonymous variants in RNASEH2A (c.69G>A and c.75C>T) create cryptic splice donor sites within exon 1. The c.69G>A variant causes an out-of-frame deletion reducing RNase H2 protein levels. The c.75C>T variant produces a truncated protein that still forms a heterotrimeric RNase H2 complex but lacks catalytic activity; leaky splicing produces a small amount of full-length active protein. Molecular (RT-PCR/splicing analysis), biochemical (catalytic activity assay), and cellular evidence including protein complex assembly assays Human mutation High 23592335
2013 RNASEH2A is the catalytic subunit of the heterotrimeric RNase H2 complex. Its truncation (from a splice site mutation) abolishes catalytic activity while still permitting heterotrimeric complex formation with RNASEH2B and RNASEH2C. Biochemical reconstitution and catalytic activity assay of mutant vs. wild-type complexes Human mutation High 23592335
2009 siRNA knockdown of RNASEH2A inhibits anchorage-independent growth of cancer cell lines but does not alter in vitro proliferation of cancer cell lines, normal mesenchymal stem cells, or normal fibroblasts, indicating a cancer-cell-specific role in anchorage-independent growth. siRNA knockdown, soft-agar anchorage-independent growth assay, proliferation assay Molecular cancer therapeutics Medium 19139135
2016 Knockdown of RNASEH2A in glioblastoma cell lines (U87 and U251) impairs cell proliferation, blocks cell cycle in G0/G1 phase, reduces colony formation, increases apoptosis (~4.5-fold), and reduces tumor growth in a mouse xenograft model. Microarray analysis indicates RNASEH2A modulates IL-6 and FAS signaling pathways. shRNA knockdown, MTT assay, flow cytometry (cell cycle and apoptosis), colony formation assay, mouse xenograft model, microarray gene expression Oncology reports Medium 27176716
2019 HPV E7 increases RNASEH2A expression in an E2F1-dependent manner in human keratinocytes, establishing a transcriptional regulatory axis (E7→E2F1→RNASEH2A). HPV E6/E7 expression in human vaginal and foreskin keratinocytes, gene expression analysis; E2F1 dependency established by knockdown/rescue mBio Medium 30696738
2024 Zebrafish rnaseh2a knockout adults accumulate ribonucleotides in brain and testes but survive to adulthood. Second-generation offspring of rnaseh2a-/- fish exhibit increased ribonucleotide incorporation, upregulated inflammatory markers, and embryonic lethality via ribodysgenesis (rapid removal of rNMPs followed by lethal DNA fragmentation), demonstrating that RNaseH2a is essential for genome stability and that its loss triggers innate immune activation. Zebrafish genetic knockout model, ribonucleotide incorporation assay, inflammatory marker quantification, embryonic viability assays, generational crosses Nucleic acids research High 39217460
2022 Lymphoblastoid cell lines from RNASEH2A-mutated AGS patients show mitochondrial morphological alterations, loss of mitochondrial membrane potential, and metabolic dysfunction (assessed by Seahorse analyzer), suggesting RNASEH2A loss leads to mitochondrial damage that may contribute to inflammatory pathway activation. Transmission electron microscopy, flow cytometry (ROS, membrane potential), Seahorse metabolic analyzer, immunofluorescence (8-oxoGuanine, VDAC1), western blot, RT-qPCR in patient-derived LCLs International journal of molecular sciences Medium 36430958
2023 SP1 transcription factor directly binds the RNASEH2A promoter and transcriptionally upregulates RNASEH2A expression in hepatocellular carcinoma cell lines; the SP1/RNASEH2A axis promotes HCC cell proliferation, cell cycle progression, migration, invasion, and epithelial-to-mesenchymal transition (EMT). Dual-luciferase reporter assay, ChIP assay, RNA interference, cell proliferation/migration/invasion assays, western blot for EMT markers Heliyon Medium 37520960
2023 ELK3 transcription factor directly binds the RNASEH2A promoter to upregulate RNASEH2A expression in glioma cells; overexpression of RNASEH2A rescues the reduction in stemness and oxaliplatin resistance caused by ELK3 knockdown, placing RNASEH2A downstream of ELK3 in this resistance pathway. Dual-luciferase reporter assay, ChIP assay, siRNA knockdown, overexpression rescue experiments, CCK-8 viability, sphere formation assay, western blot Hormone and metabolic research Medium 36638810
2021 Mass spectrometry analysis of RNASEH2A-bound proteins identifies interactors functioning in cell cycle regulation, supporting a role for RNASEH2A in cell cycle control beyond its canonical role in RNA:DNA hybrid processing. Mass spectrometry proteomics of RNASEH2A-associated proteins, bioinformatics co-expression analysis Biology Low 33805806

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American journal of medical genetics. Part A 507 25604658
2013 Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. The Lancet. Neurology 371 24183309
2009 Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets. Molecular cancer therapeutics 68 19139135
2019 Genome-Wide Profiling of Cervical RNA-Binding Proteins Identifies Human Papillomavirus Regulation of RNASEH2A Expression by Viral E7 and E2F1. mBio 55 30696738
2016 RNaseH2A is involved in human gliomagenesis through the regulation of cell proliferation and apoptosis. Oncology reports 19 27176716
2013 Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome. Human mutation 17 23592335
2005 Destabilization of tetranucleotide repeats in Haemophilus influenzae mutants lacking RnaseHI or the Klenow domain of PolI. Nucleic acids research 16 15653640
2013 Cas3 stimulates runaway replication of a ColE1 plasmid in Escherichia coli and antagonises RNaseHI. RNA biology 13 23406879
2021 Long noncoding RNA LINC01287 promotes proliferation and inhibits apoptosis of lung adenocarcinoma cells via the miR-3529-5p/RNASEH2A axis under the competitive endogenous RNA pattern. Environmental toxicology 12 34254728
2022 Characterization of Mitochondrial Alterations in Aicardi-Goutières Patients Mutated in RNASEH2A and RNASEH2B Genes. International journal of molecular sciences 10 36430958
2021 Gene Co-Expression Analysis of Human RNASEH2A Reveals Functional Networks Associated with DNA Replication, DNA Damage Response, and Cell Cycle Regulation. Biology 7 33805806
2023 SP1/RNASEH2A accelerates the development of hepatocellular carcinoma by regulating EMT. Heliyon 3 37520960
2023 Transcription Factor ELK3 Promotes Stemness and Oxaliplatin Resistance of Glioma Cells by Regulating RNASEH2A. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 2 36638810
2024 Second generation lethality in RNAseH2a knockout zebrafish. Nucleic acids research 0 39217460
2023 In Silico Characterization of RNASEH2A Pathogenic Variants and Identification of Novel Splice Site Donor Variant c.549+1G>T in Indian Population. Cureus 0 37456470

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