SYCE3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000801 central element	IBA GO_REF:0000033	ACCEPT	Summary: SYCE3 localization to the central element of the synaptonemal complex is strongly supported by structural and biochemical evidence. SYCE3 forms 2:1 heterotrimers with SYCP1 and integrates into the central element to establish the mature SC structure [PMID:36635604]. Reason: Central element localization is a core function of SYCE3. The IBA annotation is based on phylogenetic inference (including mouse ortholog MGI:MGI:1922709) and is fully consistent with direct biochemical and structural evidence from PMID:36635604 and PMID:31023827. Supporting Evidence: PMID:36635604 SYCE3 remodels and integrates into the SYCP1 lattice, establishing binding sites that cooperativity recruit SYCE1-SIX6OS1 and SYCE2-TEX12 PMID:31023827 SYCE3 adopts a dimeric four-helical bundle structure that acts as the building block for concentration-dependent self-assembly into a series of discrete higher-order oligomers
GO:0007130 synaptonemal complex assembly	IBA GO_REF:0000033	ACCEPT	Summary: SYCE3 is required for synaptonemal complex assembly, and plays an active role in remodeling the SYCP1 lattice to form the mature SC structure. This is a core function well-supported by mouse knockout studies and biochemical analyses [PMID:36635604]. Reason: Synaptonemal complex assembly is the primary biological process function of SYCE3. The IBA annotation accurately captures SYCE3's essential role in SC formation, supported by mouse Syce3-/- and Syce3WY/WY mutant phenotypes showing defective SC assembly and meiotic arrest. Supporting Evidence: PMID:36635604 SYCE3 has an essential role in actively remodelling SYCP1 tetramer lattices during the early stages of synapsis PMID:36635604 SYCE3 remodels SYCP1 tetramer lattices into integrated SYCP1-SYCE3 lattices that support full SC maturation
GO:0007131 reciprocal meiotic recombination	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: While SYCE3 is required for proper SC formation which is necessary for meiotic recombination, the role in reciprocal recombination is indirect. SYCE3's primary function is in structural remodeling of the SC lattice, not direct participation in recombination. Reason: Reciprocal meiotic recombination is a downstream consequence of SYCE3's role in SC assembly. The SC provides the structural framework for DSB repair and crossover formation, but SYCE3 itself is not directly involved in the recombination machinery. This annotation reflects the phenotypic consequence rather than the direct molecular function. Supporting Evidence: PMID:36635604 The mature SC structure then provides the necessary three-dimensional framework for DSB repair and crossover formation
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Nuclear localization is consistent with SYCE3's function in the synaptonemal complex, which assembles in the nucleus during meiotic prophase. Reason: Nuclear localization is accurate and expected for a synaptonemal complex component. While this is a general localization term, it is correctly annotated and does not represent over-annotation. Supporting Evidence: PMID:36635604 a supramolecular protein structure, the synaptonemal complex (SC), which binds homologous chromosomes together
GO:0005694 chromosome	IEA GO_REF:0000120	ACCEPT	Summary: Chromosome localization is accurate for SYCE3, which localizes to chromosomes as part of the synaptonemal complex. The more specific term GO:0000801 (central element) better captures SYCE3's precise localization. Reason: Chromosome localization is correct and represents a broader cellular component term that encompasses SYCE3's more specific localization to the central element. Both annotations are valid at different levels of specificity. Supporting Evidence: PMID:36635604 a supramolecular protein structure, the synaptonemal complex (SC), which binds homologous chromosomes together
GO:0007130 synaptonemal complex assembly	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate annotation for synaptonemal complex assembly with IEA evidence. This is consistent with the IBA annotation and experimentally validated function. Reason: While this is a duplicate of the IBA annotation with different evidence, both are valid. The IEA annotation provides computational support for the experimentally-verified core function. Supporting Evidence: PMID:36635604 SYCE3 has an essential role in actively remodelling SYCP1 tetramer lattices during the early stages of synapsis
GO:0007131 reciprocal meiotic recombination	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Duplicate IEA annotation for reciprocal meiotic recombination. As with the IBA annotation, this represents a downstream consequence of SYCE3's role in SC assembly. Reason: Consistent with the IBA annotation review - recombination is downstream of SYCE3's core SC assembly function. The annotation is not incorrect but reflects phenotypic consequence rather than direct function.
GO:0007283 spermatogenesis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: SYCE3 is required for male fertility and normal testis development, as shown by mouse knockout studies. However, this is a downstream phenotypic consequence of defective meiosis rather than a direct function. Reason: Spermatogenesis is affected in Syce3-/- and Syce3WY/WY mice, but this is due to meiotic arrest caused by defective SC assembly. SYCE3's direct function is in SC structural remodeling, not spermatogenesis per se. The annotation captures a phenotypic consequence rather than core function. Supporting Evidence: PMID:36635604 resultant chromosome asynapsis, spermatocyte death and infertility in males PMID:36635604 Syce3WY/WY and Syce3Δ/Δ homozygotes exhibited severely reduced testis weights and epididymal sperm counts
GO:0051301 cell division	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This annotation is derived from UniProt keyword mapping. While SYCE3 functions during meiotic cell division, the term 'cell division' is too general and does not accurately capture SYCE3's specific role in synaptonemal complex assembly. Reason: Cell division is an overly broad term for SYCE3. SYCE3 functions specifically in meiotic chromosome synapsis during meiotic prophase I, not in cell division generally. The more specific terms (GO:0007130 synaptonemal complex assembly, GO:0051321 meiotic cell cycle) are more appropriate.
GO:0051321 meiotic cell cycle	IEA GO_REF:0000043	ACCEPT	Summary: SYCE3 functions during the meiotic cell cycle, specifically during prophase I when the synaptonemal complex assembles. This annotation is accurate but less specific than 'synaptonemal complex assembly'. Reason: Meiotic cell cycle is an appropriate general biological process term for SYCE3. The annotation correctly places SYCE3 in the meiotic context without being overly specific or overly general. It complements the more specific SC assembly annotation. Supporting Evidence: PMID:36635604 In meiosis, haploid germ cells are formed through the segregation of homologous chromosomes following their genetic exchange by crossing over
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This annotation derives from high-throughput interactome mapping (HI-II-14). The specific interactors detected (HAUS1, BLOC1S6) are not related to SYCE3's known core function in synaptonemal complex assembly. These may represent non-specific or false positive interactions from the Y2H screen. Reason: High-throughput interactome studies often detect interactions that are not functionally relevant. SYCE3's characterized protein interactions are with SC components (SYCP1, SYCE1-SIX6OS1, SYCE2-TEX12). The 'protein binding' term is uninformative without specifying the biologically relevant binding partners. The detected interactions (HAUS1, BLOC1S6) lack validation in the context of SYCE3's meiotic function.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a study examining missense variant effects on protein-protein interactions. SYCE3-HAUS1 interaction was tested but this interaction is not relevant to SYCE3's known SC function. Reason: Same rationale as PMID:25416956 annotation. The 'protein binding' term from high-throughput studies does not provide insight into SYCE3's core molecular function. SYCE3's functionally relevant interactions are with SC components, not HAUS1.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This annotation derives from the HuRI reference interactome map. Detected interactions include PKN1, KRT79, and SGF29, none of which are known SC components or have demonstrated functional relevance to SYCE3's meiotic function. Reason: High-throughput binary interactome mapping may detect non-functional or context-inappropriate interactions. SYCE3's expression is largely restricted to meiotic cells, and interactions with PKN1, KRT79, or SGF29 have no established biological relevance. The annotation does not inform SYCE3's core function.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a neurodegenerative disease-focused interactome study. Detected interactions include HTT (huntingtin), KLF11, NUP58, WFS1, and PRPS1. These are unlikely to be physiologically relevant given SYCE3's meiosis-specific function. Reason: The neurodegenerative disease interactome study detected SYCE3 interactions that have no biological relevance to its meiotic function. SYCE3 is testis-enriched and functions specifically in meiotic prophase. Interactions with proteins like HTT or WFS1 are likely Y2H artifacts. The generic 'protein binding' term provides no useful functional information.
GO:0000801 central element	IEA GO_REF:0000107	ACCEPT	Summary: Central element localization inferred by Ensembl Compara orthology transfer from mouse. This is consistent with experimental evidence and other annotations. Reason: This IEA annotation is redundant with the IBA annotation but correctly assigns SYCE3 to the central element based on orthology to the well-characterized mouse protein (B5KM66). The annotation is accurate for SYCE3's core cellular localization.
GO:0000794 condensed nuclear chromosome	NAS PMID:27142324 Regulating the construction and demolition of the synaptonem...	MARK AS OVER ANNOTATED	Summary: This annotation from ComplexPortal is based on a review article (Cahoon & Hawley 2016) that discusses SC regulation generally but does not provide SYCE3-specific evidence for localization to condensed chromosomes. The synaptonemal complex assembles during meiotic prophase I when chromosomes are not yet fully condensed, making this term potentially misleading. Reason: PMID:27142324 is a review article that discusses SC assembly and regulation but does not contain SYCE3-specific experimental data. The term 'condensed nuclear chromosome' is imprecise for SYCE3 because the synaptonemal complex assembles during prophase I when chromosomes are in an extended, partially condensed state rather than fully condensed. The more accurate localization terms (GO:0000801 central element, GO:0000795 synaptonemal complex) are already annotated with better evidence. The NAS evidence from a general review does not support this annotation.
GO:0000795 synaptonemal complex	NAS PMID:27142324 Regulating the construction and demolition of the synaptonem...	ACCEPT	Summary: SYCE3 is indeed a component of the synaptonemal complex. This annotation is accurate but the evidence code (NAS from review article) is suboptimal. Better evidence exists from PMID:36635604 and PMID:31023827. Reason: Synaptonemal complex localization is well-established for SYCE3 through extensive biochemical and structural studies. While the NAS evidence from a review is weak, the annotation itself is correct. SYCE3 integrates into the SC by forming heterotrimers with SYCP1. Supporting Evidence: PMID:36635604 SYCE3 remodels and integrates into the SYCP1 lattice, establishing binding sites that cooperativity recruit SYCE1-SIX6OS1 and SYCE2-TEX12
GO:0007129 homologous chromosome pairing at meiosis	NAS PMID:27142324 Regulating the construction and demolition of the synaptonem...	KEEP AS NON CORE	Summary: SYCE3 contributes to chromosome synapsis through its role in SC assembly, but 'homologous chromosome pairing' is an upstream process that precedes SC formation. Pairing is established by recombination intermediates before SYCE3 acts. Reason: Homologous chromosome pairing is established by recombination-mediated alignments before SC assembly. SYCE3's role is in converting these initial alignments into mature synapsis through SYCP1 lattice remodeling. While SYCE3 loss affects overall pairing success, the primary defect is in synapsis progression rather than initial pairing. Supporting Evidence: PMID:36635604 SC assembly is directed by the inter-homologue alignments established at recombination intermediates formed at sites of induced double-strand breaks
GO:0007131 reciprocal meiotic recombination	NAS PMID:27142324 Regulating the construction and demolition of the synaptonem...	KEEP AS NON CORE	Summary: Duplicate annotation for reciprocal meiotic recombination with NAS evidence from review article. Same assessment as IBA and IEA annotations. Reason: As noted for other evidence types, recombination is downstream of SYCE3's core function in SC structural assembly. This is a phenotypic consequence annotation.
GO:0035825 homologous recombination	NAS PMID:27142324 Regulating the construction and demolition of the synaptonem...	MODIFY	Summary: Homologous recombination is a very broad term that encompasses both mitotic and meiotic recombination. For SYCE3, the more specific term GO:0007131 (reciprocal meiotic recombination) is more appropriate. Reason: 'Homologous recombination' is too general for SYCE3, which functions specifically in meiosis. The term does not distinguish meiotic from mitotic recombination. If an annotation to recombination is retained, GO:0007131 (reciprocal meiotic recombination) is more appropriate, though this is still a downstream consequence of SC assembly. Proposed replacements: reciprocal meiotic recombination
GO:0000801 central element	ISS GO_REF:0000024	ACCEPT	Summary: Central element localization transferred by sequence similarity from mouse ortholog (UniProtKB:B5KM66). This is well-supported by direct experimental evidence. Reason: ISS annotation based on mouse ortholog is accurate. Mouse Syce3 has been extensively characterized biochemically and genetically, confirming central element localization. Human SYCE3 shares the same domain architecture and is expected to have identical localization. Supporting Evidence: PMID:36635604 SYCE3 remodels and integrates into the SYCP1 lattice, establishing binding sites that cooperativity recruit SYCE1-SIX6OS1 and SYCE2-TEX12
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: Nuclear localization transferred from mouse ortholog. This is accurate and consistent with SYCE3's function in the synaptonemal complex. Reason: Nuclear localization is expected for a synaptonemal complex component. The ISS annotation from mouse ortholog is reliable given the high conservation of SC components.
GO:0005694 chromosome	ISS GO_REF:0000024	ACCEPT	Summary: Chromosome localization transferred from mouse ortholog. Accurate but less specific than central element localization. Reason: Chromosome localization is accurate and represents a broader cellular component that includes the synaptonemal complex central element where SYCE3 resides.
GO:0007130 synaptonemal complex assembly	ISS GO_REF:0000024	ACCEPT	Summary: SC assembly function transferred from mouse ortholog. This is the core biological process function of SYCE3 and is well-supported by mouse genetic studies. Reason: Mouse Syce3-/- and Syce3WY/WY studies in PMID:36635604 provide direct genetic evidence for SYCE3's essential role in SC assembly. The ISS annotation correctly captures this core function. Supporting Evidence: PMID:36635604 Syce3WY/WY and Syce3Δ/Δ homozygotes... with testis histology indicating a severe block in meiosis
GO:0007131 reciprocal meiotic recombination	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Reciprocal meiotic recombination function transferred from mouse ortholog. This represents a downstream consequence of SYCE3's SC assembly function. Reason: Same rationale as other recombination annotations - SYCE3's direct function is in SC structural remodeling, with recombination affected as a downstream consequence of SC defects.
GO:0007283 spermatogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Spermatogenesis annotation transferred from mouse ortholog. Mouse Syce3 knockouts show male infertility, but this is a downstream phenotype of meiotic arrest. Reason: Spermatogenesis defects in Syce3 mutant mice result from meiotic arrest at pachytene, not from a direct role in spermatogenesis per se. SYCE3 functions in meiotic chromosome synapsis; the spermatogenesis defect is a phenotypic consequence. Supporting Evidence: PMID:36635604 severely reduced testis weights and epididymal sperm counts, with testis histology indicating a severe block in meiosis
GO:0005198 structural molecule activity	ISS GO_REF:0000024	NEW	Summary: SYCE3 is a structural component of the synaptonemal complex central element that forms 2:1 heterotrimers with SYCP1 and self-assembles to create an integrated SYCP1-SYCE3 lattice. Its primary molecular function is providing structural support for SC assembly and maturation, consistent with structural molecule activity [PMID:36635604, PMID:31023827]. Reason: SYCE3's core molecular function is as a structural scaffold protein in the synaptonemal complex. It forms the central element by remodeling SYCP1 tetramers and self-assembling into higher-order structures. This structural role is well-characterized biochemically and structurally (crystal structure PDB 6H86) but is not currently annotated with a molecular function term. The existing annotations focus on biological process and cellular component aspects; GO:0005198 captures the essential molecular function of SYCE3 as a structural protein. Supporting Evidence: PMID:36635604 SYCE3 remodels and integrates into the SYCP1 lattice, establishing binding sites that cooperativity recruit SYCE1-SIX6OS1 and SYCE2-TEX12 PMID:31023827 SYCE3 adopts a dimeric four-helical bundle structure that acts as the building block for concentration-dependent self-assembly into a series of discrete higher-order oligomers

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