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Showing C1ORF146 — SCRE is a alias.

C1ORF146

Protein SPO16 homolog · UniProt Q5VVC0

Length
180 aa
Mass
20.4 kDa
Annotated
2026-06-09
55 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C1ORF146/SPO16 (yeast Spo16; mouse SCRE) is an evolutionarily conserved meiosis-specific protein that promotes interference-sensitive crossover formation as a structural component of the ZZS recombination complex (PMID:18297071, PMID:29440262, PMID:30746471). Within ZZS, Spo16/SPO16 forms an XPF-ERCC1-like heterodimer with Zip2/SHOC1 that lacks endonuclease activity but binds branched DNA recombination intermediates through central and helix-hairpin-helix DNA-binding surfaces, channeling these intermediates toward crossover resolution (PMID:29440262, PMID:30566683). Zip4/TEX11 links this DNA-binding module to the chromosome axis, and SPO16 is required to stabilize SHOC1 and to scaffold recruitment of additional ZMM factors, including M1AP-dependent TEX11 loading at recombination intermediates (PMID:29440262, PMID:30746471, PMID:36440627). Genetically, Spo16 acts specifically in the interference-sensitive (Zip3/ZMM-dependent) crossover pathway and is dispensable for crossover interference itself (PMID:18297071, PMID:26305689). In mice, the same protein (SCRE) localizes as discrete foci along the synaptonemal complex central element and reinforces SC integrity through interactions with SYCP1 and SYCE3, with loss causing unstable synapsis and meiotic collapse at late zygotene (PMID:30949703). The ZZS module functions upstream of SC central-element assembly, proximity-labeling Ecm11 in a Zip4-dependent, Zip1-independent manner (PMID:39405359). In humans, biallelic loss-of-function and splicing variants in SPO16 cause meiotic arrest with defective recombination, underlying premature ovarian insufficiency and male infertility (PMID:37270785, PMID:40374915).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1990 Medium

    Identified the yeast SPO16 gene as a meiosis-specific factor required for sporulation, establishing it as a candidate meiotic gene before any mechanism was known.

    Evidence Yeast genetics and Northern blot analysis of a meiosis-specific transcript with an insertion mutation disrupting SPO12 complementarity

    PMID:2188099

    Open questions at the time
    • No molecular function assigned
    • Antisense complementarity with SPO12 shown to be functionally irrelevant
    • No protein-level characterization
  2. 2008 High

    Placed Spo16 in the ZMM crossover pathway and distinguished its role: required for crossover assurance/formation but, unusually among ZMM mutants, dispensable for interference.

    Evidence Genetic analysis of spo16 mutants (spore viability, crossover frequency, interference) plus co-IP with Zip4/Spo22 in budding yeast

    PMID:18297071

    Open questions at the time
    • Biochemical activity of Spo16 unknown
    • Structural basis of Zip4 interaction undefined
    • No mammalian counterpart yet identified
  3. 2015 Medium

    Refined Spo16's genetic placement, showing it operates in the interference-sensitive, Zip3-dependent crossover class and downstream of SC assembly to couple recombination intermediates to crossover resolution.

    Evidence Whole-genome recombination mapping, Zip3 immunofluorescence, tel1Δ double-mutant epistasis, and interspecies Zip1 complementation in budding yeast

    PMID:26114667 PMID:26305689

    Open questions at the time
    • Molecular substrate of Spo16 still unknown
    • Direct biochemical activity not tested
  4. 2018 High

    Defined the ZZS trimeric complex and showed Zip2-Spo16 resemble the XPF-ERCC1 nuclease yet bind branched DNA without cleaving it, providing the first mechanistic model — a structure-specific DNA-binding scaffold rather than a resolvase.

    Evidence Co-IP, in vitro branched-DNA binding assays, structural similarity analysis, and genetic epistasis in yeast

    PMID:29440262

    Open questions at the time
    • Atomic structure not yet solved
    • Specific DNA contact residues unmapped
    • Mammalian conservation untested at this stage
  5. 2019 High

    Solved the Zip2:Spo16 crystal structure, confirming the XPF-ERCC1-like fold lacking an active site and mapping DNA-binding surfaces whose mutation abolishes crossover formation in vivo.

    Evidence X-ray crystallography, in vitro DNA-binding assays, structure-guided mutagenesis, yeast genetics

    PMID:30566683

    Open questions at the time
    • Structure of the full ZZS trimer absent
    • Dynamics of intermediate channeling not resolved
  6. 2019 High

    Established mammalian conservation: SPO16 (C1ORF146) is the Spo16 ortholog, interacts with SHOC1 and TEX11, localizes to recombination nodules, and is required to stabilize SHOC1 and load ZMM proteins, with loss yielding crossover-defective DSB repair.

    Evidence Reciprocal co-IP, immunofluorescence, and SPO16-knockout mouse phenotyping of DSB repair and crossovers; rice OsPTD interaction studies extend conservation to plants

    PMID:30746471 PMID:31266799

    Open questions at the time
    • Quantitative DNA-binding of mammalian SPO16 not reconstituted
    • Order of SHOC1/SPO16/TEX11 assembly incompletely defined
  7. 2019 High

    Revealed a second function for the same protein (SCRE) at the synaptonemal complex central element, reinforcing SC integrity via SYCP1 and SYCE3, with loss causing SC instability and arrest at late zygotene.

    Evidence Scre-knockout mice, immunofluorescence on meiotic chromosomes, co-IP with SYCP1 and SYCE3, fertility and histology

    PMID:30949703

    Open questions at the time
    • Relationship between the SC-reinforcing role and the ZZS DNA-binding role unresolved
    • Direct binding interface with SYCP1/SYCE3 not structurally defined
  8. 2022 High

    Positioned SPO16 as an upstream scaffold for M1AP-TEX11 axis recruitment, showing SPO16 is required for M1AP localization to chromosomal axes and TEX11 loading at intermediates.

    Evidence Reciprocal co-IP of ZZS components, immunofluorescence, and knockout mouse models analyzing recombination intermediates and crossovers

    PMID:36440627

    Open questions at the time
    • Direct vs indirect SPO16-M1AP contact not distinguished
    • Stoichiometry of the M1AP-ZZS assembly unknown
  9. 2024 Medium

    Linked ZZS function to SC central-element assembly, showing Spo16/ZZS proximity-labels Ecm11 in a Zip4-dependent, Zip1-independent manner, placing the complex upstream of central-element protein loading.

    Evidence Proximity labeling (BioID/TurboID) with mass spectrometry and genetic controls in yeast

    PMID:39405359

    Open questions at the time
    • Proximity labeling does not prove direct contact
    • Mechanism coupling ZZS to Ecm11 recruitment unresolved
  10. 2025 Medium

    Established human disease relevance: biallelic SPO16 loss-of-function and a SHOC1 XPF-domain variant that impairs SPO16/TEX11 recruitment cause meiotic arrest with defective synapsis, unrepaired DSBs, and abolished crossovers, complementing the earlier premature-ovarian-insufficiency splicing variant.

    Evidence Clinical genetics, minigene splicing assay, testicular biopsy histology/immunofluorescence, meiocyte assays, and crossover analysis with patient variants

    PMID:37270785 PMID:40374915 PMID:42258546

    Open questions at the time
    • SPO16 role in human variants partly inferred from SHOC1 disruption
    • Single or limited patient cohorts per variant
    • No structural data on human SPO16

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single conserved protein mechanistically reconciles its branched-DNA-binding role within ZZS with its physical reinforcement of the SC central element remains unresolved.
  • No structure of mammalian SPO16 or the full ZZS trimer
  • Temporal/spatial switch between recombination-nodule and central-element functions undefined
  • Quantitative biochemistry of mammalian SPO16 DNA binding not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-1640170 Cell Cycle 2
Partners
ECM11M1APSHOC1SYCE3SYCP1TEX11ZIP2ZIP4
Complex memberships
ZZS complex (Zip2/SHOC1–Zip4/TEX11–Spo16/SPO16)Zip2:Spo16 (SHOC1:SPO16) heterodimersynaptonemal complex central element

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Yeast Spo16 is a ZMM protein required for meiotic crossing-over and synaptonemal complex formation; unlike other ZMM mutants, spo16 mutants retain wild-type crossover interference, indicating Spo16 is specifically required for crossover assurance but not interference. Spo16 physically interacts with the ZMM protein Spo22/Zip4. Genetic analysis of spo16 mutants (spore viability, crossover frequency, interference measurements), co-immunoprecipitation/interaction studies with Spo22/Zip4 Nature genetics High 18297071
2018 Spo16, together with Zip2 and Zip4, forms the ZZS (Zip2-Zip4-Spo16) trimeric complex in yeast. Zip2 and Spo16 share structural similarity to the XPF-ERCC1 nuclease but lack endonuclease activity; instead they preferentially bind branched DNA molecules (recombination intermediates) in vitro. The ZZS complex connects recombination events to the chromosome axis through Zip4 interactions. Co-immunoprecipitation, in vitro DNA-binding assays with branched DNA substrates, structural similarity analysis, genetic epistasis Genes & development High 29440262
2019 Crystal structure of the Zip2:Spo16 subcomplex reveals a heterodimer structurally related to the XPF:ERCC1 endonuclease complex. Zip2:Spo16 lacks an endonuclease active site but binds specific branched DNA structures present in early meiotic recombination intermediates. Mutations in multiple DNA-binding surfaces (central and HhH domains) on the Zip2:Spo16 heterodimer severely compromise DNA binding and crossover formation in vivo. X-ray crystallography, in vitro DNA-binding assays, structure-guided mutagenesis, yeast genetics Nucleic acids research High 30566683
2019 Mammalian SPO16 (C1ORF146) is the ortholog of yeast Spo16; it interacts with SHOC1 (mammalian Zip2 ortholog) and TEX11 (mammalian Zip4 ortholog). SPO16 localizes to recombination nodules and is required for stabilization of SHOC1 and proper localization of other ZMM proteins. Deletion of SPO16 in mice causes meiotic DSBs to be repaired without crossover formation, with less severe effects on synapsis. Co-immunoprecipitation, immunofluorescence localization, mouse knockout (SPO16 deletion), analysis of DSB repair and crossover formation Science advances High 30746471
2019 SCRE (synaptonemal complex reinforcing element; C1ORF146) localizes as discrete foci along the central elements of the synaptonemal complex in mice. Deletion of Scre causes unstable synapsis and SCs, meiosis collapse at the late zygotene stage, and infertility in both sexes. SCRE interacts with synaptonemal complex protein SYCP1 and central element protein SYCE3, functioning to reinforce the integrity of central elements. Mouse knockout (Scre deletion), immunofluorescence localization on meiotic chromosomes, co-immunoprecipitation with SYCP1 and SYCE3, fertility and histological analysis Nucleic acids research High 30949703
2022 M1AP interacts with the mammalian ZZS complex components SHOC1, TEX11, and SPO16. SPO16 is required for M1AP localization to chromosomal axes; M1AP colocalizes with TEX11 and promotes TEX11 recruitment to recombination intermediates. This positions SPO16 as a scaffolding component upstream of M1AP-TEX11 axis recruitment. Co-immunoprecipitation, immunofluorescence localization, mouse knockout models, analysis of recombination intermediates and crossovers EMBO reports High 36440627
1990 Yeast SPO16 gene (adjacent to SPO12 on opposite DNA strand) is required for efficient spore formation during meiosis; its transcript is meiosis-specific and partially complementary to SPO12 mRNA, though the complementarity itself was shown to have no functional role in meiosis. Yeast genetics, Northern blot analysis, insertion mutation disrupting complementarity Molecular and cellular biology Medium 2188099
2015 In budding yeast, Spo16 (as part of ZMM) is required for Zip3-dependent crossover formation; in a tel1Δ background, ZMM-independent crossovers increase, indicating Spo16/ZMM pathway crossovers are a distinct class. Zip3 foci in tel1Δ cells show normal interference, consistent with Spo16 functioning specifically in the interference-sensitive crossover pathway. Whole-genome recombination mapping, immunofluorescence (Zip3 foci), double-mutant analysis (tel1Δ zip3Δ) PLoS genetics Medium 26305689
2015 In budding yeast, K. lactis Zip1-mediated crossovers rely on S. cerevisiae Spo16 (as well as Zip3, Zip4, and Mlh3), demonstrating that Spo16 is required downstream of SC assembly for crossover formation and is part of the pathway that couples recombination intermediates to SC assembly. Interspecies complementation genetics, spore viability assays, immunofluorescence for SC proteins PLoS genetics Medium 26114667
2019 Rice SPO16 ortholog OsPTD interacts with the Zip2 ortholog OsSHOC1 and with OsHEI10, and is required for the same set of crossover formations as OsSHOC1. Bimolecular fluorescence complementation and yeast-three-hybrid assays showed OsSHOC1, OsPTD, OsHEI10, and OsZIP4 can form various heterotrimeric combinations, conserving the ZZS complex function in plants. Yeast two-hybrid, bimolecular fluorescence complementation (BiFC), yeast three-hybrid, immunofluorescence localization, plant knockout genetics Plant physiology Medium 31266799
2023 A homozygous splicing variant in SPO16 (c.160+8A>G) produces a non-functional SPO16 protein (verified by minigene splicing assay) and is associated with premature ovarian insufficiency, establishing that SPO16 function (binding branched DNA and recruiting ZMM proteins for crossover formation) is essential for ovarian maintenance in humans. Whole-exome sequencing, minigene splicing assay, clinical genetic analysis Clinical genetics Medium 37270785
2024 Proximity labeling in yeast demonstrates that Spo16 (as part of the ZZS complex) proximity-labels Ecm11 (SC central element protein) in a Zip4-dependent and Zip1-independent manner, placing ZZS upstream of Ecm11 in SC assembly independently of Zip1. Proximity labeling (BioID/TurboID), mass spectrometry, yeast genetics PLoS genetics Medium 39405359
2025 In human/mouse meiosis, SHOC1 forms a trimeric ZZS complex with SPO16 and TEX11 to bind recombination intermediates after strand invasion. A missense variant in the XPF-like domain of SHOC1 (p.Q590R) impairs branched-DNA binding and reduces SPO16/TEX11 recruitment to recombination intermediates, abolishing crossover formation. This study establishes that SPO16 depends on SHOC1's XPF-like domain for proper recruitment. Clinical variant analysis, mouse and human meiocyte immunofluorescence, chromatin immunoprecipitation, 3D chromatin structure analysis, crossover assays Nucleic acids research Medium 42258546
2025 Men with biallelic loss-of-function variants in ZZS genes (including SPO16) show early meiotic arrest characterized by incorrect synapsis of homologous chromosomes, unrepaired DNA double-strand breaks, and incomplete recombination — distinct from M1AP deficiency phenotype, establishing SPO16 as essential for early meiotic recombination progression in humans. Clinical genetic screening, testicular biopsy histology and immunofluorescence, comparison of meiotic arrest phenotypes across genotypes EMBO molecular medicine Medium 40374915

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Crossover assurance and crossover interference are distinctly regulated by the ZMM proteins during yeast meiosis. Nature genetics 182 18297071
2012 Simple few-state models reveal hidden complexity in protein folding. Proceedings of the National Academy of Sciences of the United States of America 139 22778442
2018 A meiotic XPF-ERCC1-like complex recognizes joint molecule recombination intermediates to promote crossover formation. Genes & development 78 29440262
2011 VCre/VloxP and SCre/SloxP: new site-specific recombination systems for genome engineering. Nucleic acids research 71 21288882
2023 Amelioration effects of α-viniferin on hyperuricemia and hyperuricemia-induced kidney injury in mice. Phytomedicine : international journal of phytotherapy and phytopharmacology 57 37209608
2006 Probing molecular docking in a charged model binding site. Journal of molecular biology 50 16490206
2005 Behavioral risk exposure and host genetics of susceptibility to HIV-1 infection. The Journal of infectious diseases 46 16323127
1972 Mutant of Escherichia coli K-12 deficient for detergent-resistant phospholipase A. Journal of bacteriology 44 4555415
1990 Complementary transcripts from two genes necessary for normal meiosis in the yeast Saccharomyces cerevisiae. Molecular and cellular biology 42 2188099
2019 Arrhythmia mechanisms and spontaneous calcium release: Bi-directional coupling between re-entrant and focal excitation. PLoS computational biology 39 31393876
2015 Reduced Crossover Interference and Increased ZMM-Independent Recombination in the Absence of Tel1/ATM. PLoS genetics 39 26305689
2015 Separable Crossover-Promoting and Crossover-Constraining Aspects of Zip1 Activity during Budding Yeast Meiosis. PLoS genetics 33 26114667
2019 SPO16 binds SHOC1 to promote homologous recombination and crossing-over in meiotic prophase I. Science advances 32 30746471
2018 Evolutionarily-conserved MZIP2 is essential for crossover formation in mammalian meiosis. Communications biology 30 30272023
1995 Protective effects of KW-3902, an adenosine A1-receptor antagonist, against cisplatin-induced acute renal failure in rats. Japanese journal of pharmacology 30 7650867
2019 The conserved XPF:ERCC1-like Zip2:Spo16 complex controls meiotic crossover formation through structure-specific DNA binding. Nucleic acids research 29 30566683
2014 Urine neutrophil gelatinase-associated lipocalin to predict acute kidney injury in preterm neonates. A pilot study. Pediatric nephrology (Berlin, Germany) 27 24022367
1993 Genetic and molecular analysis of REC114, an early meiotic recombination gene in yeast. Current genetics 27 8385581
2019 A Multiprotein Complex Regulates Interference-Sensitive Crossover Formation in Rice. Plant physiology 20 31266799
2019 SCRE serves as a unique synaptonemal complex fastener and is essential for progression of meiosis prophase I in mice. Nucleic acids research 18 30949703
2022 M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination. EMBO reports 17 36440627
2011 Recombinase-mediated cassette exchange (RMCE) and BAC engineering via VCre/VloxP and SCre/SloxP systems. BioTechniques 17 21548907
2009 Temperature-dependent modulation of chromosome segregation in msh4 mutants of budding yeast. PloS one 17 19816584
2017 Cell adhesion molecule-1 shedding induces apoptosis of renal epithelial cells and exacerbates human nephropathies. American journal of physiology. Renal physiology 16 29070574
2023 Exploration of the anti-hyperuricemia effect of TongFengTangSan (TFTS) by UPLC-Q-TOF/MS-based non-targeted metabonomics. Chinese medicine 15 36797795
2018 Improving the efficiency of gene insertion in a human artificial chromosome vector and its transfer in human-induced pluripotent stem cells. Biology methods & protocols 14 32161806
2013 The lack of benefit of a combination of an angiotensin receptor blocker and calcium channel blocker on contrast-induced nephropathy in patients with chronic kidney disease. Renal failure 14 23413781
2015 Acute Kidney Injury and Rhabdomyolysis After Protobothrops flavoviridis Bite: A Retrospective Survey of 86 Patients in a Tertiary Care Center. The American journal of tropical medicine and hygiene 13 26643529
2012 Clinical impact of the leptin to soluble leptin receptor ratio on subclinical carotid atherosclerosis in patients with type 2 diabetes. Journal of atherosclerosis and thrombosis 13 23124060
2003 Radiocontrast-induced nephrotoxicity and urinary alpha-glutathione S-transferase levels: effect of amlodipine administration. International urology and nephrology 13 15072506
2016 Foodomics study on the effects of extracellular production of hydrogen peroxide by rosemary polyphenols on the anti-proliferative activity of rosemary polyphenols against HT-29 cells. Electrophoresis 12 26842614
2014 Smilax china L. rhizome extract inhibits nuclear factor-κB and induces apoptosis in ovarian cancer cells. Chinese journal of integrative medicine 12 25511428
1996 Effects of cisplatin on erythropoietin production in rats. The Journal of toxicological sciences 11 8887884
2020 Renal expression and urinary excretion of liver-type fatty acid-binding protein in cats with renal disease. Journal of veterinary internal medicine 10 32087614
2023 Protective Potential of Saussurea costus (Falc.) Lipsch. Roots against Cyclophosphamide-Induced Pulmonary Injury in Rats and Its In Vitro Antiviral Effect. Pharmaceuticals (Basel, Switzerland) 9 37259460
2012 Construction of homologous and heterologous synthetic sucrose utilizing modules and their application for carotenoid production in recombinant Escherichia coli. Bioresource technology 9 23313673
2018 Novel reporter and deleter mouse strains generated using VCre/VloxP and SCre/SloxP systems, and their system specificity in mice. Transgenic research 7 29546522
2024 Proximity labeling reveals new functional relationships between meiotic recombination proteins in S. cerevisiae. PLoS genetics 6 39405359
2023 Lessons from the meiotic recombination landscape of the ZMM deficient budding yeast Lachancea waltii. PLoS genetics 6 36608114
2019 Deletion of Ck2β gene causes germ cell development arrest and azoospermia in male mice. Cell proliferation 6 31755150
2023 Pathogenic bi-allelic variants of meiotic ZMM complex gene SPO16 in premature ovarian insufficiency. Clinical genetics 5 37270785
2021 Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model. Clinical and experimental nephrology 5 33728555
2021 Full composition granules of Huanglian (Rhizoma Coptidis) decrease the serum monocyte chemotactic protein-1 and connective tissue growth factor levels and inhibit kidney nuclear factor-κB expression in rats with high-fat diet-induced diabete. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan 5 34114400
2016 In vivo recombination efficiency of two site-specific recombination systems, VCre/VloxP and SCre/SloxP, in medaka (Oryzias latipes). Development, growth & differentiation 5 27224047
2023 VCre/VloxP and SCre/SloxP as Reliable Site-Specific Recombination Systems for Genome Engineering. Methods in molecular biology (Clifton, N.J.) 3 36773146
2024 TSCRE: a comprehensive database for tumor-specific cis-regulatory elements. NAR cancer 2 38213995
2025 Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes. EMBO molecular medicine 1 40374915
2025 Crossover formation and coordinated assembly of synaptonemal complex relies on a direct interaction between Zip1 and Zip3. bioRxiv : the preprint server for biology 1 41332580
2023 A Case of Bariatric Surgery for a Japanese Kidney Transplant Recipient With Diabetes Mellitus: A Case Report. Transplantation proceedings 1 37524583
2026 Crossover formation and coordinated assembly of synaptonemal complex relies on a direct interaction between Zip1 and Zip3. Genetics 0 41894234
2026 XPF-like domain in human SHOC1 is required for crossover formation and protecting autosome from MSUC. Nucleic acids research 0 42258546
2025 Is the TEX11-.652del237bp Exonic In-Frame Deletion Variant Associated with Azoospermia? The Results of an In Vitro and In Silico Study. Genes 0 41300722
2024 Production of a bacterial secretome highly efficient for the deconstruction of xylans. World journal of microbiology & biotechnology 0 38997527
2023 A Case of Kidney Transplantation from a Deceased Donor with Acute Kidney Injury due to Rhabdomyolysis. Nephron 0 36966535
2012 Albuminuria-reducing effect of angiotensin II receptor blocker plus hydrochlorothiazide combination therapy in renal transplant recipients. Experimental and therapeutic medicine 0 23060931

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