Affinage

ELAC2

Zinc phosphodiesterase ELAC protein 2 · UniProt Q9BQ52

Length
826 aa
Mass
92.2 kDa
Annotated
2026-06-09
48 papers in source corpus 15 papers cited in narrative 15 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

ELAC2 is the human tRNase Z (zinc phosphodiesterase) responsible for endonucleolytic removal of the 3' trailer from pre-tRNAs, an essential step in both nuclear and mitochondrial tRNA maturation (PMID:21593607, PMID:21146608). Cryo-EM structures of apo, pre-tRNA-bound, and tRNA-bound enzyme establish the catalytic mechanism: a flexible arm domain recruits the pre-tRNA and a conformational rearrangement of the C-terminal helix feeds the 3' trailer into the active center for cleavage (PMID:39494506). Dual subcellular targeting is achieved through alternative translation initiation: use of the first AUG generates a full-length, mitochondrially targeted protein, while initiation from the second AUG yields a product lacking the mitochondrial targeting sequence that is routed to the nucleus (PMID:21559454, PMID:21593607). In mitochondria, loss-of-function mutations abolish 3'-end processing of multiple mt-tRNAs and impair mitochondrial translation, and complementation with wild-type ELAC2 restores processing, defining the enzyme as causative for infantile hypertrophic cardiomyopathy with complex I deficiency (PMID:23849775, PMID:31045291). Beyond core tRNA processing, ELAC2 partners with the helicase SUPV3L1 to degrade mitochondria-encoded circular RNAs (PMID:39973625), and it has been linked to G2-M cell cycle progression through interaction with the gamma-tubulin complex (PMID:12569551) and to TGF-beta/Smad signaling, where it associates with activated Smad2, FAST-1, and Sp1 to potentiate p21 induction and growth arrest (PMID:16636667).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 Medium

    Before ELAC2's enzymatic role was established, this work tied the protein to cell-cycle control, showing it interacts with the gamma-tubulin complex and influences G2-M progression.

    Evidence Biochemical pulldown/Co-IP and cyclin B accumulation analysis in tumor cells

    PMID:12569551

    Open questions at the time
    • No reciprocal Co-IP or structural validation of the gamma-tubulin interaction
    • Mechanistic link between the interaction and G2-M delay unresolved
    • Relationship to the later-defined tRNase Z activity not addressed
  2. 2005 Medium

    Yeast and in vitro studies addressed whether catalytic residues matter and whether disease variants alter enzyme function, establishing conserved active-site requirements while finding prostate-cancer variants enzymatically silent.

    Evidence Yeast TRZ1 genetic suppression/complementation with active-site mutagenesis, plus recombinant ELAC2 kinetic (Km/kcat) assays of cancer variants

    PMID:15863270 PMID:15892892

    Open questions at the time
    • Negative kinetic result from a single lab
    • Conserved histidine/P-loop requirement shown in yeast ortholog, not directly in human enzyme
    • Did not resolve substrate identity in human cells
  3. 2006 Medium

    This study extended ELAC2 beyond RNA processing into signaling, showing it scaffolds TGF-beta/Smad transcriptional output to drive growth arrest.

    Evidence Reciprocal domain-mapping Co-IP, siRNA knockdown, luciferase reporter, and growth arrest assays in prostate cells

    PMID:16636667

    Open questions at the time
    • Single lab
    • Connection between nuclear scaffolding role and tRNA-processing function not integrated
    • In vivo relevance of p21 potentiation unknown
  4. 2011 High

    These studies defined ELAC2's core molecular function as the mitochondrial tRNA 3'-end endonuclease and explained its dual localization through alternative translation initiation.

    Evidence siRNA knockdown with RT-PCR/northern detection of mt-tRNA processing intermediates; GFP-fusion imaging with alternative start-codon mutagenesis

    PMID:21559454 PMID:21593607

    Open questions at the time
    • Catalytic mechanism not yet resolved structurally
    • Regulation of AUG choice between compartments not characterized
  5. 2013 High

    Complementation rescue established causality between ELAC2 loss-of-function, unprocessed mt-RNA accumulation, and infantile hypertrophic cardiomyopathy with complex I deficiency.

    Evidence Patient cell/tissue RNA analysis, complementation in mutant cell lines, yeast model

    PMID:23849775

    Open questions at the time
    • Why cardiac tissue is selectively vulnerable not explained
    • Genotype-phenotype correlations across variants not mapped
  6. 2016 Medium

    A patient splicing mutation reducing ELAC2 expression confirmed the human RNA-processing defect in disease and broadened the mutational spectrum.

    Evidence Whole-exome sequencing, homozygosity mapping, RT-PCR and northern blot of patient fibroblasts

    PMID:27769300

    Open questions at the time
    • Single case series
    • Hypomorphic versus null contribution to phenotype not dissected
  7. 2019 High

    In vitro enzymatic testing of disease variants directly linked impaired RNase Z activity to cardiomyopathy and showed a prostate-cancer-associated variant also reduces activity.

    Evidence In vitro RNase Z activity assays with recombinant mutants, structural modeling, patient fibroblast northern blot

    PMID:31045291

    Open questions at the time
    • Quantitative threshold of activity loss causing disease not defined
    • Reconciliation with earlier negative kinetic result for some variants not addressed
  8. 2021 Medium

    Three studies expanded ELAC2's RNA-related repertoire beyond canonical tRNA processing: mitochondrial mecciRNA degradation, a viral-induced tRNA fragment, and in vivo confirmation of cardiomyopathy variant pathogenicity.

    Evidence SUPV3L1/ELAC2 co-complex identification with RNA-seq; ELAC2 knockdown and viral protein Co-IP for tRF5-GlnCTG induction during RSV infection; transgenic Drosophila cardiac phenotyping

    PMID:33604354 PMID:34338278 PMID:39973625

    Open questions at the time
    • SUPV3L1 complex lacks detailed orthogonal Co-IP validation
    • tRF5-GlnCTG activity is a novel ELAC2 function from a single lab
    • Mechanistic basis for fragment generation versus trailer cleavage unclear
  9. 2024 High

    Cryo-EM structures resolved the long-standing question of how ELAC2 engages and cleaves pre-tRNA, defining the arm-domain recruitment and C-terminal helix feeding mechanism and rationalizing disease mutations.

    Evidence Cryo-EM in apo, pre-tRNA-bound and tRNA-bound states with biochemical cleavage and disease-variant assays

    PMID:39494506

    Open questions at the time
    • Structural basis for nuclear versus mitochondrial substrate specificity not addressed
    • Structure of the mecciRNA-degrading SUPV3L1/ELAC2 complex not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the catalytic tRNase Z core relates mechanistically to ELAC2's reported non-canonical roles in gamma-tubulin/cell-cycle control and TGF-beta/Smad transcriptional scaffolding remains unresolved.
  • No structural or biochemical bridge between catalytic and signaling functions
  • Non-canonical roles rest on single-lab studies
  • Whether nuclear ELAC2 acts catalytically or as a scaffold in these contexts is unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005739 mitochondrion 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3
Partners
FAST-1SMAD2SP1SUPV3L1
Complex memberships
SUPV3L1/ELAC2 mecciRNA degradation complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 ELAC2 functions as tRNase Z in human mitochondria, responsible for 3' end processing of mitochondrial tRNAs. Silencing ELAC2 by siRNA resulted in impaired 3' end processing of multiple mt-tRNAs (tRNA-Val, tRNA-Lys, tRNA-Arg, tRNA-Gly, tRNA-Leu(UUR), tRNA-Glu) encoded on both mtDNA strands, establishing its role as the mitochondrial 3'-end endonuclease. siRNA knockdown, RT-PCR, northern blot analysis RNA biology High 21593607
2011 ELAC2 exhibits dual nuclear/mitochondrial localization. Alternative translation initiation from the second AUG of ELAC2 mRNA (due to unfavorable context of the first AUG) produces a protein lacking the mitochondrial targeting sequence, which is routed to the nucleus instead. The full-length protein (translation from the first AUG) localizes to mitochondria. GFP fusion protein expression, fluorescence microscopy, immunofluorescence, alternative start codon mutagenesis PloS one High 21559454 21593607
2013 Mutations in ELAC2 cause accumulation of mitochondrial RNA precursors (unprocessed mt-tRNA 3' ends) and impaired mitochondrial translation, leading to infantile hypertrophic cardiomyopathy and complex I deficiency. Complementation of mutant cell lines with wild-type ELAC2 restored RNA processing, establishing causality. Patient cell/tissue RNA analysis, complementation experiments in mutant cell lines, yeast model American journal of human genetics High 23849775
2003 ELAC2 physically interacts with the gamma-tubulin complex. Overexpression of ELAC2 in tumor cells causes a delay in G2-M progression with accumulation of cyclin B levels. Biochemical pulldown/co-immunoprecipitation, cell cycle analysis (cyclin B accumulation) International journal of cancer Medium 12569551
2006 ELAC2 associates with activated Smad2 via an interaction between the C-terminal MH2 domain of Smad2 and the N-terminal region of ELAC2. ELAC2 also associates with the nuclear Smad2 partner FAST-1 and potentiates the interaction of activated Smad2 with transcription factor Sp1. siRNA-mediated knockdown of ELAC2 suppresses TGF-beta-induced growth arrest in prostate cells, and ELAC2 potentiates activation of the p21 CDK inhibitor promoter by TGF-beta. Co-immunoprecipitation, domain mapping, siRNA knockdown, luciferase reporter assay, growth arrest assay Oncogene Medium 16636667
2005 The yeast ELAC2 homolog TRZ1 is involved in RNA processing in vivo. A trz1 deletion mutant's temperature sensitivity is rescued by multiple copies of REX2 (encoding an RNA 3' processing protein). The conserved histidine motif and C-terminal P-loop nucleotide-binding motif of Trz1p are essential for function, as mutations in these motifs abolish complementation. Yeast genetic suppression screen, plasmid-based complementation, site-directed mutagenesis BMC molecular biology Medium 15892892
2005 Recombinant ELAC2 protein bearing the prostate cancer-associated missense variants (Ser217Leu, Ala541Thr, Arg781His) showed no differences in enzymatic properties (Km and kcat values) compared to wild-type tRNase ZL in pre-tRNA cleavage and RNase 65 activity assays. Recombinant protein production, in vitro enzymatic assay (Km, kcat determination) Cancer letters Medium 15863270
2019 Novel ELAC2 missense variants associated with hypertrophic cardiomyopathy impair mitochondrial RNase Z activity as demonstrated in an in vitro system. The prostate cancer-associated variant p.Arg781His also impairs mitochondrial RNase Z activity of ELAC2. Primary fibroblasts from affected individuals exhibit elevated levels of unprocessed mitochondrial RNA precursors. In vitro RNase Z activity assay with recombinant mutant proteins, structural modeling, northern blot of patient fibroblast RNA Human mutation High 31045291
2004 Drosophila RNAi knockdown of dRNaseZ (ELAC2 homolog) demonstrated it is essential for 3'-end processing of both nuclear and mitochondrial tRNAs in vivo, causing accumulation of processing intermediates with 3' extensions. Knockdown in mitotically growing imaginal discs impaired cell proliferation/viability; in endoreplicating salivary glands it reduced cell growth but not DNA replication. Heritable RNAi (GAL4/UAS system), molecular analysis of tRNA processing intermediates, tissue-specific phenotypic analysis Insect biochemistry and molecular biology Medium 21146608
2004 The C. elegans ELAC2 homolog hoe-1 is required for germline proliferation. RNAi knockdown caused sterility due to drastic reduction in germline proliferation and cell-cycle arrest of germline nuclei. hoe-1 was required for hyperproliferation phenotypes from mutations in three different genes, and hoe-1 RNAi suppressed the multivulva phenotype from activating ras mutations (likely indirectly). RNAi knockdown, genetic epistasis analysis with germline proliferation mutants and ras gain-of-function mutants Developmental biology Medium 14729485
2024 Cryo-EM structures of human ELAC2 in apo, pre-tRNA-bound, and tRNA-bound states revealed the structural basis for pre-tRNA binding and 3' trailer cleavage. The flexible arm domain recruits pre-tRNA; conformational rearrangement of the C-terminal helix feeds the 3' trailer into the active center for cleavage. Biochemical assays confirmed structural effects of disease-related mutations on ELAC2 activity. Cryo-EM structure determination, biochemical cleavage assays, disease-variant functional analysis Nucleic acids research High 39494506
2021 ELAC2 forms a complex with the helicase SUPV3L1 to degrade mitochondria-encoded circular RNAs (mecciRNAs). This SUPV3L1/ELAC2 degradation complex is animal-conserved and is responsible for the fast degradation of mecciRNAs in mitochondria. RNA sequencing, molecular and biochemical experiments, co-complex identification Circulation Medium 39973625
2021 ELAC2 is responsible for the induction of a tRNA-derived RNA fragment (tRF5-GlnCTG) from mature tRNA-Gln-CTG during respiratory syncytial virus (RSV) infection. ELAC2 is also associated with RSV N and NS1 proteins, and tRF5-GlnCTG produced via ELAC2 promotes RSV replication. Northern blot, qRT-PCR, siRNA knockdown of ELAC2, co-immunoprecipitation with RSV proteins Frontiers in molecular biosciences Medium 33604354
2021 Expression of Drosophila RNaseZ carrying CM-linked mutations (equivalent to human ELAC2 cardiomyopathy mutations) in flies with endogenous RNaseZ knockout caused cardiac hypertrophy and reduced cardiac contractility, providing direct experimental evidence for pathogenicity of these ELAC2 variants. Transgenic Drosophila with endogenous knockout background, cardiac phenotype analysis Disease models & mechanisms Medium 34338278
2016 A homozygous splicing mutation in ELAC2 (c.1423+2T>A) disrupts the canonical donor splice site of intron 15, reduces ELAC2 expression, and causes significantly increased levels of 5'-end unprocessed mt-RNAs in patient fibroblasts, confirming ELAC2's role in mt-RNA 3' processing in human disease. Whole-exome sequencing, homozygosity mapping, RT-PCR for ELAC2 expression, northern blot for unprocessed mt-RNAs in patient fibroblasts Orphanet journal of rare diseases Medium 27769300

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Involvement of human ELAC2 gene product in 3' end processing of mitochondrial tRNAs. RNA biology 168 21593607
2000 Association of HPC2/ELAC2 genotypes and prostate cancer. American journal of human genetics 123 10986046
2013 ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. American journal of human genetics 117 23849775
2011 Localization of human RNase Z isoforms: dual nuclear/mitochondrial targeting of the ELAC2 gene product by alternative translation initiation. PloS one 85 21559454
2001 Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. American journal of human genetics 85 11254448
2001 Role of HPC2/ELAC2 in hereditary prostate cancer. Cancer research 79 11522646
2001 ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer. Cancer research 64 11507049
2003 The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the gamma-tubulin complex. International journal of cancer 61 12569551
2005 Characterization of TRZ1, a yeast homolog of the human candidate prostate cancer susceptibility gene ELAC2 encoding tRNase Z. BMC molecular biology 60 15892892
2001 Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Cancer research 51 11431329
2006 ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-beta/Smad-induced growth arrest of prostate cells. Oncogene 46 16636667
2003 ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer. Journal of the National Cancer Institute 46 12783937
2019 Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing. Human mutation 41 31045291
2010 Single and multivariate associations of MSR1, ELAC2, and RNASEL with prostate cancer in an ethnic diverse cohort of men. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 40 20086112
2004 The Caenorhabditis elegans homolog of the putative prostate cancer susceptibility gene ELAC2, hoe-1, plays a role in germline proliferation. Developmental biology 34 14729485
2002 HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease. British journal of cancer 34 12373607
2010 ELAC2 polymorphisms and prostate cancer risk: a meta-analysis based on 18 case-control studies. Prostate cancer and prostatic diseases 30 20231859
2005 The missense mutations in the candidate prostate cancer gene ELAC2 do not alter enzymatic properties of its product. Cancer letters 21 15863270
2017 The Phenotype and Outcome of Infantile Cardiomyopathy Caused by a Homozygous ELAC2 Mutation. Cardiology 20 28441660
2002 Association of common missense changes in ELAC2 ( HPC2) with prostate cancer in a Japanese case-control series. Journal of human genetics 20 12522685
2025 Fast Degradation of MecciRNAs by SUPV3L1/ELAC2 Provides a Novel Opportunity to Tackle Heart Failure With Exogenous MecciRNA. Circulation 19 39973625
2021 ELAC2, an Enzyme for tRNA Maturation, Plays a Role in the Cleavage of a Mature tRNA to Produce a tRNA-Derived RNA Fragment During Respiratory Syncytial Virus Infection. Frontiers in molecular biosciences 17 33604354
2004 Mutational analysis of susceptibility genes RNASEL/HPC1, ELAC2/HPC2, and MSR1 in sporadic prostate cancer. Genes, chromosomes & cancer 17 14695991
2003 Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men. International journal of cancer 17 12949798
2002 ELAC2 and prostate cancer risk in Afro-Caribbeans of Tobago. Human genetics 17 12384782
2005 Characterization of linkage disequilibrium structure, mutation history, and tagging SNPs, and their use in association analyses: ELAC2 and familial early-onset prostate cancer. Genetic epidemiology 14 15593091
2016 A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement. Orphanet journal of rare diseases 13 27769300
2010 RNAi knockdown of dRNaseZ, the Drosophila homolog of ELAC2, impairs growth of mitotic and endoreplicating tissues. Insect biochemistry and molecular biology 13 21146608
2004 Structure of primate and rodent orthologs of the prostate cancer susceptibility gene ELAC2. Biochimica et biophysica acta 12 15358515
2003 HPC2/ELAC2 gene variants associated with incident prostate cancer. Journal of human genetics 12 14625808
2002 Association of HPC2/ELAC2 polymorphism with prostate cancer risk in a Japanese population. Anticancer research 12 12552947
2011 A survey of green plant tRNA 3'-end processing enzyme tRNase Zs, homologs of the candidate prostate cancer susceptibility protein ELAC2. BMC evolutionary biology 11 21781332
2010 Identification and analysis of candidate fungal tRNA 3'-end processing endonucleases tRNase Zs, homologs of the putative prostate cancer susceptibility protein ELAC2. BMC evolutionary biology 11 20819227
2004 HPC2/ELAC2 polymorphism associated with Japanese sporadic prostate cancer. The Prostate 11 15368467
2021 ELAC2/RNaseZ-linked cardiac hypertrophy in Drosophila melanogaster. Disease models & mechanisms 9 34338278
2001 Loss of heterozygosity of the putative prostate cancer susceptibility gene HPC2/ELAC2 is uncommon in sporadic and familial prostate cancer. Cancer research 9 11751379
2011 Associations of polymorphisms in HPC2/ELAC2 and SRD5A2 genes with benign prostate hyperplasia in Turkish men. Asian Pacific journal of cancer prevention : APJCP 8 21627373
2008 Sequence variants of elaC homolog 2 (Escherichia coli) (ELAC2) gene and susceptibility to prostate cancer in the Health Professionals Follow-Up Study. Carcinogenesis 8 18375959
2024 Structural insights into human ELAC2 as a tRNA 3' processing enzyme. Nucleic acids research 7 39494506
2023 Novel ELAC2 Mutations in Individuals Presenting with Variably Severe Neurological Disease in the Presence or Absence of Cardiomyopathy. Life (Basel, Switzerland) 6 36836802
2019 Nuclear ELAC2 overexpression is associated with increased hazard for relapse after radical prostatectomy. Oncotarget 6 31452838
2019 Prevalence of the Ser217Leu Variant of the ELAC2 Gene and Its Association with Prostate Cancer in Population of the Littoral Region of Cameroon. Prostate cancer 4 31321101
2023 ELAC2 Functions as a Key Gene in the Early Development of Placental Formation Based on WGCNA. Cells 3 36831280
2023 ELAC2 is a functional prostate cancer risk allele. Trends in molecular medicine 2 37353407
2022 Carriage of Ser217Leu and Ala541Thr Variants of ELAC2 Gene and Risk Factors in Patients with Prostate Cancer in Burkina Faso. Prostate cancer 2 36643816
2011 Polymorphisms of HPC2/ELAC2 and SRD5A2 (5α-Reductase Type II) Genes in Prostate Cancer. Balkan journal of medical genetics : BJMG 2 24052700
2022 Pseudohypoaldosteronism associated with hypertrophic cardiomyopathy, hypertension and thrombocytosis due to mutation in the ELAC2 gene: a case report. Journal of pediatric endocrinology & metabolism : JPEM 1 35946480
2023 Microcystin-leucine-arginine promotes the development of gallbladder carcinoma via regulating ELAC2. Biochemical and biophysical research communications 0 37329658

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