NUC1 encodes the budding yeast mitochondrial EndoG-family nuclease, a metal-dependent DNA/RNA nuclease that resides at the mitochondrial inner membrane and accounts for most nonspecific nuclease activity in mitochondria. It acts in mitochondrial nucleic-acid turnover and mitochondrial DNA recombination, can degrade mitochondrial DNA destined for mitophagy-associated vacuolar escape, and is released from mitochondria into the cytosol during sporulation to attenuate L-A and Killer double-stranded RNA mycoviruses. Nuc1 also has a conserved apoptotic nuclease role: mitochondrial release, nuclear import, and chromatin association of Nuc1 drive yeast apoptotic death in overexpression and respiration-dependent death contexts, and Nuc1 is required for apoptotic-like DNA laddering of discarded meiotic nuclei during gametogenesis. Nuc1 is also needed for the viability of polyploid cells: deletion of NUC1 eliminates tetraploid cells during exponential growth, by an unknown mechanism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000423 mitophagy | IMP PMID:41638207 The mitochondrial intermembrane space nuclease Nuc1 (endonuc... | MODIFY | Summary: Nuc1 degrades mitochondrial DNA exposed to a mitophagy-linked vacuolar escape route, but the nuclease is cargo-side quality control rather than core mitophagy machinery. Reason: Cupo et al. showed that loss of NUC1 permits mtDNA escape through a pathway requiring Atg11/Atg32-mediated mitophagy and vacuolar entry, placing Nuc1 on mtDNA degradation during mitophagy rather than on selective mitochondrial capture itself. Replace the pathway label with mitochondrial DNA catabolic process. Proposed replacements: mitochondrial DNA catabolic process Supporting Evidence: PMID:41638207 Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape PMID:41638207 blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | MODIFY | Summary: Nucleic acid binding is correct for an EndoG-family nuclease but less informative than Nuc1's DNA and RNA nuclease activities. Reason: The InterPro domain supports catalytic nuclease activity, and Nuc1 has direct DNA endonuclease and RNA nuclease evidence. Replace the generic binding row with the catalytic terms. Proposed replacements: DNA endonuclease activity RNA endonuclease activity Supporting Evidence: PMID:3286639 The purified enzyme shows multiple activities: 1) RNase activity on single-stranded, but not double-stranded RNA, 2) endonuclease activity on single- and double-stranded DNA, and 3) a 5'-exonuclease activity on double-stranded DNA. |
| GO:0004520 DNA endonuclease activity | IBA GO_REF:0000033 | ACCEPT | Summary: Nuc1 is a conserved EndoG-family nuclease with DNA endonuclease activity. Reason: The PAINT transfer is supported by Nuc1's placement in the EndoG-related PANTHER family and by direct purification of the yeast mitochondrial enzyme showing endonuclease activity on single- and double-stranded DNA. Supporting Evidence: PMID:3286639 endonuclease activity on single- and double-stranded DNA |
| GO:0004520 DNA endonuclease activity | IDA PMID:3286639 Purification and properties of the major nuclease from mitoc... | ACCEPT | Summary: Nuc1 is the major yeast mitochondrial DNA endonuclease. Reason: The purified 38 kDa mitochondrial Nuc1 enzyme directly cleaves DNA endonucleolytically, and disrupting NUC1 eliminated detectable mitochondrial DNase activity. Supporting Evidence: PMID:3286639 endonuclease activity on single- and double-stranded DNA PMID:3286639 all detectable DNase activity and most nonspecific RNase activity in the mitochondria is due to this single enzyme |
| GO:0004520 DNA endonuclease activity | IEA GO_REF:0000117 | ACCEPT | Summary: Nuc1 is the major yeast mitochondrial DNA endonuclease. Reason: The ARBA DNA-endonuclease inference is consistent with direct Nuc1 purification and with the conserved EndoG-like family assignment. Supporting Evidence: PMID:3286639 endonuclease activity on single- and double-stranded DNA |
| GO:0004520 DNA endonuclease activity | IMP PMID:41638207 The mitochondrial intermembrane space nuclease Nuc1 (endonuc... | ACCEPT | Summary: Nuc1 nuclease activity degrades mtDNA that otherwise escapes through a mitophagy-associated route. Reason: The 2026 mtDNA-escape study showed that Nuc1 catalytic activity is required to prevent mitochondrial DNA escape, supporting a DNA nuclease activity in this physiological context. Supporting Evidence: PMID:41638207 Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape |
| GO:0004521 RNA endonuclease activity | IBA GO_REF:0000033 | ACCEPT | Summary: Nuc1 belongs to the conserved EndoG nuclease family and has RNA nuclease activity. Reason: The PAINT RNA-endonuclease call is consistent with the direct biochemical finding that the purified yeast mitochondrial enzyme cleaves single-stranded RNA. Supporting Evidence: PMID:3286639 RNase activity on single-stranded, but not double-stranded RNA |
| GO:0004529 DNA exonuclease activity | IDA PMID:3286639 Purification and properties of the major nuclease from mitoc... | ACCEPT | Summary: Purified Nuc1 has a 5-prime exonuclease activity on double-stranded DNA. Reason: In addition to its endonuclease activities, the isolated mitochondrial enzyme showed 5-prime exonuclease activity and was later genetically implicated in enlarging heteroduplex tracts during mitochondrial DNA recombination. Supporting Evidence: PMID:3286639 5'-exonuclease activity PMID:8087883 5' exonuclease activity of the NUC1 nuclease functions during recombination |
| GO:0004540 RNA nuclease activity | IDA PMID:3286639 Purification and properties of the major nuclease from mitoc... | ACCEPT | Summary: Purified Nuc1 cleaves single-stranded RNA and accounts for most nonspecific mitochondrial RNase activity. Reason: Direct purification of the major yeast mitochondrial nuclease showed RNase activity on single-stranded RNA and loss of most mitochondrial nonspecific RNase activity after NUC1 disruption. Supporting Evidence: PMID:3286639 RNase activity on single-stranded, but not double-stranded RNA PMID:3286639 all detectable DNase activity and most nonspecific RNase activity in the mitochondria is due to this single enzyme |
| GO:0004540 RNA nuclease activity | IEA GO_REF:0000117 | ACCEPT | Summary: Purified Nuc1 cleaves single-stranded RNA and accounts for most nonspecific mitochondrial RNase activity. Reason: The ARBA RNA-nuclease prediction is consistent with the direct activity of the purified yeast mitochondrial enzyme. Supporting Evidence: PMID:3286639 RNase activity on single-stranded, but not double-stranded RNA |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: EndoG-family nucleases can act in the nucleus during apoptotic DNA fragmentation, and yeast Nuc1 is imported into the nucleus in a death-associated context. Reason: PAINT places nuclear EndoG activity at the same ancestral node that includes Nuc1, and the yeast apoptotic Nuc1 paper requires nuclear import and chromatin association for Nuc1-mediated death. Supporting Evidence: PMID:17244531 nuclear import, and chromatin association are successively involved in EndoG-mediated death |
| GO:0005634 nucleus | IDA PMID:17244531 Endonuclease G regulates budding yeast life and death. | ACCEPT | Summary: Nuc1 can localize to the nucleus in an EndoG-like apoptotic death pathway. Reason: Buttner et al. directly connected Nuc1 nuclear import and chromatin association to yeast apoptotic death upon Nuc1 overexpression. Supporting Evidence: PMID:17244531 nuclear import, and chromatin association are successively involved in EndoG-mediated death |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | KEEP AS NON CORE | Summary: Nuc1 is a mitochondrial inner-membrane nuclease. Reason: The high-throughput mitochondrial proteome row is consistent with direct biochemical localization of Nuc1 to the mitochondrial inner membrane and with UniProt's curated mitochondrial inner-membrane annotation, but mitochondrion is broader than the core inner-membrane location. Supporting Evidence: PMID:3286639 in the mitochondrial inner membrane file:yeast/NUC1/NUC1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane. |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | KEEP AS NON CORE | Summary: Nuc1 is a mitochondrial inner-membrane nuclease. Reason: The phosphoproteomic isolated-mitochondria row is consistent with direct biochemical localization of Nuc1 to the mitochondrial inner membrane and with UniProt's curated mitochondrial inner-membrane annotation, but mitochondrion is broader than the core inner-membrane location. Supporting Evidence: PMID:3286639 in the mitochondrial inner membrane file:yeast/NUC1/NUC1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane. |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Nuc1 is a mitochondrial inner-membrane nuclease. Reason: The ARBA mitochondrial localization is supported by direct purification of Nuc1 from yeast mitochondria and direct placement of the enzyme at the mitochondrial inner membrane, but it is less precise than the curated inner-membrane rows. Supporting Evidence: PMID:3286639 in the mitochondrial inner membrane |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Nuc1 is active at the mitochondrial inner membrane. Reason: Direct biochemical localization places Nuc1 in the mitochondrial inner membrane, matching the inherited EndoG-family inner-membrane activity placement. Supporting Evidence: PMID:3286639 in the mitochondrial inner membrane file:yeast/NUC1/NUC1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:17244531 Endonuclease G regulates budding yeast life and death. | ACCEPT | Summary: Nuc1 is mitochondrial before its death-associated release and nuclear import. Reason: Although only the abstract is cached locally, SGD's full-text IDA row is consistent with direct evidence that Nuc1 is normally a mitochondrial inner-membrane nuclease and is released from mitochondria in meiotic yeast. Supporting Evidence: PMID:3286639 in the mitochondrial inner membrane PMID:31266891 budding yeast executes meiotically programmed mitochondrial release of |
| GO:0005743 mitochondrial inner membrane | IDA PMID:3286639 Purification and properties of the major nuclease from mitoc... | ACCEPT | Summary: Nuc1 is located in the mitochondrial inner membrane. Reason: The original purification study directly localized the bulk of yeast mitochondrial nuclease activity, attributable to Nuc1, to the inner membrane. Supporting Evidence: PMID:3286639 in the mitochondrial inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Nuc1 is located in the mitochondrial inner membrane. Reason: The UniProt subcellular-location mapping is consistent with direct yeast mitochondrial inner-membrane localization. Supporting Evidence: PMID:3286639 in the mitochondrial inner membrane file:yeast/NUC1/NUC1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane. |
| GO:0005829 cytosol | IDA PMID:31266891 Meiotic viral attenuation through an ancestral apoptotic pat... | ACCEPT | Summary: Nuc1 is released into the cytosol during sporulation. Reason: Gao et al. detected programmed cytosolic accumulation of Nuc1-FLAG during yeast meiosis, placing the EndoG-family nuclease in the same compartment as the L-A and Killer dsRNA mycoviruses it attenuates. Supporting Evidence: PMID:31266891 Beginning at the 6-h time point and persisting through the postmeiotic 10-h time point, we detected robust Nuc1-FLAG accumulation in concentrated cytosolic fractions |
| GO:0006308 DNA catabolic process | IDA PMID:3286639 Purification and properties of the major nuclease from mitoc... | ACCEPT | Summary: Nuc1 directly degrades DNA as the major mitochondrial DNase. Reason: The purified mitochondrial enzyme has DNA endonuclease and 5-prime exonuclease activities, and NUC1 disruption removed detectable mitochondrial DNase activity. Supporting Evidence: PMID:3286639 all detectable DNase activity and most nonspecific RNase activity in the mitochondria is due to this single enzyme |
| GO:0006309 apoptotic DNA fragmentation | IBA GO_REF:0000033 | ACCEPT | Summary: Nuc1 has a conserved EndoG-like role in death-associated DNA fragmentation. Reason: The PAINT inference is supported both by conserved EndoG-family nuclease biology and by yeast gametogenesis data showing that NUC1 is required for apoptotic-like nucleosomal DNA laddering of discarded meiotic nuclei. Supporting Evidence: PMID:31266891 where their DNA is fragmented into nucleosomal ladders in a manner requiring NUC1 |
| GO:0006309 apoptotic DNA fragmentation | IMP PMID:22727375 Developmentally programmed nuclear destruction during yeast ... | ACCEPT | Summary: NUC1 is required for apoptotic-like DNA fragmentation of discarded meiotic nuclei. Reason: The Developmental Cell paper established apoptotic-like programmed nuclear destruction during yeast gametogenesis, and the later full-text PNAS paper states that meiotic nuclei are fragmented into nucleosomal ladders in a manner requiring NUC1. Supporting Evidence: PMID:22727375 PND is executed through apoptotic-like DNA fragmentation PMID:31266891 where their DNA is fragmented into nucleosomal ladders in a manner requiring NUC1 |
| GO:0006310 DNA recombination | IMP PMID:8087883 Analysis of the role of the NUC1 endo/exonuclease in yeast m... | KEEP AS NON CORE | Summary: NUC1 promotes efficient mitochondrial DNA recombination. Reason: Zassenhaus and Denniger showed reduced mitochondrial DNA recombination and lower gene-conversion frequencies in NUC1-deficient yeast and proposed that Nuc1's 5-prime exonuclease activity acts after mitochondrial DNA double-strand breaks. This is a real downstream role for the mitochondrial nuclease but secondary to its core DNA/RNA cleavage activity. Supporting Evidence: PMID:8087883 Mitochondrial DNA recombination was reduced in an yeast mutant lacking the NUC1 endo/exonuclease PMID:8087883 5' exonuclease activity of the NUC1 nuclease functions during recombination |
| GO:0006401 RNA catabolic process | IDA PMID:3286639 Purification and properties of the major nuclease from mitoc... | KEEP AS NON CORE | Summary: Nuc1 directly degrades RNA as the major mitochondrial nonspecific RNase. Reason: Purified Nuc1 cleaves single-stranded RNA, and NUC1 disruption removed most nonspecific RNase activity from mitochondria. The activity is real, but this broad process row does not yet resolve a specific physiological mitochondrial RNA-decay pathway. Supporting Evidence: PMID:3286639 RNase activity on single-stranded, but not double-stranded RNA PMID:3286639 all detectable DNase activity and most nonspecific RNase activity in the mitochondria is due to this single enzyme |
| GO:0006915 apoptotic process | IMP PMID:17244531 Endonuclease G regulates budding yeast life and death. | ACCEPT | Summary: Nuc1 can drive yeast apoptotic death after mitochondrial release and nuclear import. Reason: The yeast EndoG homolog supports an experimentally defined apoptosis-like pathway in which mitochondrial pore opening, nuclear import, and chromatin association of Nuc1 are required for Nuc1-mediated death, so the generic yeast apoptotic-process row is appropriate. Supporting Evidence: PMID:17244531 Nuc1p induces apoptosis in yeast PMID:17244531 Deletion of NUC1 diminishes apoptotic death when mitochondrial respiration is increased but enhances necrotic death when oxidative phosphorylation is repressed |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | MODIFY | Summary: General hydrolase activity is true but much less informative than Nuc1's nuclease activities. Reason: InterPro maps the EndoG nuclease domain to a generic hydrolase parent; direct yeast evidence supports more specific DNA endonuclease, DNA exonuclease, and RNA nuclease annotations. Proposed replacements: DNA endonuclease activity RNA nuclease activity Supporting Evidence: PMID:3286639 The purified enzyme shows multiple activities: 1) RNase activity on single-stranded, but not double-stranded RNA, 2) endonuclease activity on single- and double-stranded DNA, and 3) a 5'-exonuclease activity on double-stranded DNA. |
| GO:0016788 hydrolase activity, acting on ester bonds | IEA GO_REF:0000117 | MODIFY | Summary: General ester hydrolase activity is true but much less informative than Nuc1's nuclease activities. Reason: Nucleases are phosphodiester hydrolases, but the ARBA term should be narrowed to the directly supported DNA and RNA nuclease activities. Proposed replacements: DNA endonuclease activity RNA nuclease activity Supporting Evidence: PMID:3286639 The purified enzyme shows multiple activities: 1) RNase activity on single-stranded, but not double-stranded RNA, 2) endonuclease activity on single- and double-stranded DNA, and 3) a 5'-exonuclease activity on double-stranded DNA. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Nuc1 is a metal-dependent EndoG-family nuclease. Reason: Nuc1 requires Mg(2+) or Mn(2+) as a catalytic cofactor, consistent with the InterPro metal-binding prediction for the nuclease domain; metal binding supports the nuclease chemistry but is not the primary activity. Supporting Evidence: file:yeast/NUC1/NUC1-uniprot.txt Name=Mg(2+); Xref=ChEBI:CHEBI:18420; file:yeast/NUC1/NUC1-uniprot.txt The active site contains 1 hydrated divalent metal |
| GO:0051607 defense response to virus | IDA PMID:31266891 Meiotic viral attenuation through an ancestral apoptotic pat... | ACCEPT | Summary: Meiotic cytosolic Nuc1 attenuates L-A and Killer dsRNA mycoviruses in budding yeast. Reason: During sporulation, Nuc1 is released from mitochondria into the cytosol and its nuclease activity protects meiotic progeny by collaborating with the SKI pathway to attenuate Killer/L-A virus accumulation. Supporting Evidence: PMID:31266891 attenuating the cytosolic L-A and Killer double-stranded RNA mycoviruses |
| GO:1901858 regulation of mitochondrial DNA metabolic process | IMP PMID:41638207 The mitochondrial intermembrane space nuclease Nuc1 (endonuc... | MODIFY | Summary: Nuc1 prevents mitophagy-linked mtDNA escape by degrading mitochondrial DNA rather than by regulating mtDNA metabolism indirectly. Reason: The 2026 study argues for direct nuclease degradation of mtDNA bound for escape; this is mitochondrial DNA catabolism, not regulation of another mitochondrial DNA metabolic activity. Proposed replacements: mitochondrial DNA catabolic process Supporting Evidence: PMID:41638207 suggest a direct role of Nuc1 in degrading mtDNA bound for escape |
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Download this section (compressed HTML)Q: Should the 2026 Nuc1 mtDNA-escape evidence be curated as mitochondrial DNA catabolism with a mitophagy/vacuole extension rather than as Nuc1 participation in mitophagy?
Suggested experts: Youle R, Cupo RR
Q: Should fungal EndoG-family apoptotic DNA fragmentation stay under generic apoptotic process, or should GO add a fungal meiotic programmed nuclear destruction descendant to separate this biology from canonical metazoan execution?
Suggested experts: Meneghini MD
Experiment: Purify meiotic cytosolic Nuc1-RNP complexes from wild-type and H138A nuclease-dead strains, identify bound viral RNAs by RT-qPCR or RNA sequencing, and compare L-A/M1 RNA cleavage products in wild-type, nuc1-null, and nuclease-dead sporulating cells.
Hypothesis: Cytosolic Nuc1 attenuates L-A and Killer viruses by directly cleaving viral dsRNA or a viral replication intermediate during meiosis.
Type: nuclease substrate mapping
Experiment: Follow mtDNA escape reporters and mitophagy flux in nuc1 catalytic and mitochondrial-localization mutants, with and without ATG15, to distinguish failed mtDNA degradation from altered delivery of mitochondria to the vacuole.
Hypothesis: During mitophagy, Nuc1 degrades mtDNA before or during vacuolar autophagic-body breakdown rather than regulating the core Atg11/Atg32 mitophagy pathway.
Type: epistasis and live-cell mtDNA reporter assay
Major mitochondrial nuclease; has RNAse and DNA endo- and exonucleolytic activities; prevents genome instability by degrading extranuclear DNA sequences; roles in mitochondrial recombination, apoptosis and maintenance of polyploidy; involved in fragmentation of genomic DNA during PND (programmed nuclear destruction); role in preventing L-A mycovirus pathogenesis; encodes ortholog of mammalian endoG
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