{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:36:09Z","timestamp":1779338169033,"version":"3.51.4"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rep.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,4,1]]},"abstract":"<jats:title>\u2003<\/jats:title>\n                  <jats:sec>\n                    <jats:title>In brief<\/jats:title>\n                    <jats:p>The dissociation of HORMA domain protein 2 (HORMAD2) from the synaptonemal complex is tightly regulated. This study reveals that the N-terminal region of HORMAD2 is critical for its dissociation from synapsed meiotic chromosomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>During meiosis, homologous chromosomes undergo synapsis and recombination. HORMA domain proteins regulate key processes in meiosis. Mammalian HORMAD1 and HORMAD2 localize to unsynapsed chromosome axes but are removed upon synapsis by the TRIP13 AAA+ ATPase. TRIP13 engages the N-terminal region of HORMA domain proteins to induce an open conformation, resulting in the disassembly of protein complexes. Here, we report introduction of a 3\u00d7FLAG-HA tag to the N-terminus of HORMAD2 in mice. Coimmunoprecipitation coupled with mass spectrometry identified HORMAD1 and SYCP2 as HORMAD2-associated proteins in the testis. Unexpectedly, the N-terminal tagging of HORMAD2 resulted in its abnormal persistence along synapsed regions in pachynema and ectopic localization to telomeres in diplonema. Super-resolution microscopy revealed that 3\u00d7FLAG-HA-HORMAD2 was distributed along the central region of the synaptonemal complex, whereas wild-type HORMAD1 persisted along the lateral elements in 3\u00d7FLAG-HA-HORMAD2 meiocytes. Although homozygous mice completed meiosis and were fertile, homozygous males exhibited a significant reduction in sperm count. Collectively, these results suggest that the N-terminus of HORMAD2 is important for its timely removal from meiotic chromosome axes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/rep-23-0330","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T12:15:51Z","timestamp":1708604151000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-11","source":"Crossref","is-referenced-by-count":3,"title":["The N-terminal modification of HORMAD2 causes its ectopic persistence on synapsed chromosomes without meiotic blockade"],"prefix":"10.1093","volume":"167","author":[{"given":"Isabella G","family":"Cossu","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences , University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N Adrian","family":"Leu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences , University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongjuan","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences , University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA"},{"name":"College of Life Sciences , Capital Normal University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2311-4089","authenticated-orcid":false,"given":"P Jeremy","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences , University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"2026010712103206900_bib1","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1038\/s41586-018-0281-1","article-title":"Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13","volume":"559","author":"Alfieri","year":"2018","journal-title":"Nature"},{"key":"2026010712103206900_bib2","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1083\/jcb.200610027","article-title":"SYCE2 is required for synaptonemal complex assembly, double strand break repair, and homologous recombination","volume":"176","author":"Bolcun-Filas","year":"2007","journal-title":"Journal of Cell Biology"},{"key":"2026010712103206900_bib3","doi-asserted-by":"publisher","first-page":"e1000393","DOI":"10.1371\/journal.pgen.1000393","article-title":"Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair","volume":"5","author":"Bolcun-Filas","year":"2009","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib4","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1126\/science.1247671","article-title":"Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway","volume":"343","author":"Bolcun-Filas","year":"2014","journal-title":"Science"},{"key":"2026010712103206900_bib5","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1083\/jcb.201311050","article-title":"BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis","volume":"205","author":"Broering","year":"2014","journal-title":"Journal of Cell Biology"},{"key":"2026010712103206900_bib6","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.cell.2008.01.035","article-title":"Phosphorylation of the axial element protein Hop1 by Mec1\/Tel1 ensures meiotic interhomolog recombination","volume":"132","author":"Carballo","year":"2008","journal-title":"Cell"},{"key":"2026010712103206900_bib7","doi-asserted-by":"publisher","first-page":"E44","DOI":"10.1073\/pnas.1310755111","article-title":"Pch2 is a hexameric ring ATPase that remodels the chromosome axis protein Hop1","volume":"111","author":"Chen","year":"2014","journal-title":"PNAS"},{"key":"2026010712103206900_bib8","doi-asserted-by":"publisher","DOI":"10.1101\/2023.09.25.559355","article-title":"TRIP13 localizes to synapsed chromosomes and functions as a dosage-sensitive regulator of meiosis","author":"Chotiner","year":"2023","journal-title":"bioRxiv"},{"key":"2026010712103206900_bib9","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1126\/science.1083022","article-title":"Essential role of Fkbp6 in male fertility and homologous chromosome pairing in meiosis","volume":"300","author":"Crackower","year":"2003","journal-title":"Science"},{"key":"2026010712103206900_bib10","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/ncb2213","article-title":"Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1","volume":"13","author":"Daniel","year":"2011","journal-title":"Nature Cell Biology"},{"key":"2026010712103206900_bib11","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1101\/gad.329705","article-title":"Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation","volume":"19","author":"de Vries","year":"2005","journal-title":"Genes and Development"},{"key":"2026010712103206900_bib12","doi-asserted-by":"publisher","first-page":"e1009048","DOI":"10.1371\/journal.pgen.1009048","article-title":"Meiotic cohesins mediate initial loading of HORMAD1 to the chromosomes and coordinate SC formation during meiotic prophase","volume":"16","author":"Fujiwara","year":"2020","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib13","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.yexcr.2009.08.007","article-title":"A novel mammalian HORMA domain-containing protein, HORMAD1, preferentially associates with unsynapsed meiotic chromosomes","volume":"316","author":"Fukuda","year":"2010","journal-title":"Experimental Cell Research"},{"key":"2026010712103206900_bib14","doi-asserted-by":"publisher","first-page":"e1002485","DOI":"10.1371\/journal.pgen.1002485","article-title":"Phosphorylation of chromosome core components may serve as axis marks for the status of chromosomal events during mammalian meiosis","volume":"8","author":"Fukuda","year":"2012","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib15","doi-asserted-by":"publisher","first-page":"13298","DOI":"10.1038\/ncomms13298","article-title":"C14ORF39\/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility","volume":"7","author":"Gomez","year":"2016","journal-title":"Nature Communications"},{"key":"2026010712103206900_bib16","doi-asserted-by":"publisher","first-page":"eaaz2129","DOI":"10.1126\/sciadv.aaz2129","article-title":"SKP1 drives the prophase I to metaphase I transition during male meiosis","volume":"6","author":"Guan","year":"2020","journal-title":"Science Advances"},{"key":"2026010712103206900_bib17","doi-asserted-by":"publisher","first-page":"5129","DOI":"10.1093\/nar\/gkac304","article-title":"SCF ubiquitin E3 ligase regulates DNA double-strand breaks in early meiotic recombination","volume":"50","author":"Guan","year":"2022","journal-title":"Nucleic Acids Research"},{"key":"2026010712103206900_bib18","doi-asserted-by":"publisher","first-page":"4025","DOI":"10.1242\/jcs.03182","article-title":"Characterization of a novel meiosis-specific protein within the central element of the synaptonemal complex","volume":"119","author":"Hamer","year":"2006","journal-title":"Journal of Cell Science"},{"key":"2026010712103206900_bib19","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/nrg2723","article-title":"Genetics of mammalian meiosis: regulation, dynamics and impact on fertility","volume":"11","author":"Handel","year":"2010","journal-title":"Nature Reviews.Genetics"},{"key":"2026010712103206900_bib20","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/0092-8674(9090216-2","article-title":"The HOP1 gene encodes a meiosis-specific component of yeast chromosomes","volume":"61","author":"Hollingsworth","year":"1990","journal-title":"Cell"},{"key":"2026010712103206900_bib21","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2026010712103206900_bib22","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.devcel.2014.09.013","article-title":"The chromosome axis controls meiotic events through a hierarchical assembly of HORMA domain proteins","volume":"31","author":"Kim","year":"2014","journal-title":"Developmental Cell"},{"key":"2026010712103206900_bib23","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1111\/gtc.12005","article-title":"HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity","volume":"17","author":"Kogo","year":"2012","journal-title":"Genes to Cells: Devoted to Molecular and Cellular Mechanisms"},{"key":"2026010712103206900_bib24","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1111\/j.1365-2443.2012.01600.x","article-title":"HORMAD1-dependent checkpoint\/surveillance mechanism eliminates asynaptic oocytes","volume":"17","author":"Kogo","year":"2012","journal-title":"Genes to Cells"},{"key":"2026010712103206900_bib25","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1128\/mcb.14.2.1137-1146.1994","article-title":"The gene encoding a major component of the lateral elements of synaptonemal complexes of the rat is related to X-linked lymphocyte-regulated genes","volume":"14","author":"Lammers","year":"1994","journal-title":"Molecular and Cellular Biology"},{"key":"2026010712103206900_bib26","doi-asserted-by":"publisher","first-page":"e130","DOI":"10.1371\/journal.pgen.0030130","article-title":"Mouse pachytene checkpoint 2 (trip13) is required for completing meiotic recombination but not synapsis","volume":"3","author":"Li","year":"2007","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib27","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/nsmb748","article-title":"The Mad2 spindle checkpoint protein has two distinct natively folded states","volume":"11","author":"Luo","year":"2004","journal-title":"Nature Structural and Molecular Biology"},{"key":"2026010712103206900_bib28","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1023\/a:1018445520117","article-title":"A drying-down technique for the spreading of mammalian meiocytes from the male and female germline","volume":"5","author":"Peters","year":"1997","journal-title":"Chromosome Research"},{"key":"2026010712103206900_bib29","doi-asserted-by":"publisher","DOI":"10.3390\/genes13050777","article-title":"Functions and regulation of meiotic HORMA-domain proteins","volume":"13","author":"Prince","year":"2022","journal-title":"Genes"},{"key":"2026010712103206900_bib30","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/j.molcel.2017.07.027","article-title":"The DNA damage checkpoint eliminates mouse oocytes with chromosome synapsis failure","volume":"67","author":"Rinaldi","year":"2017","journal-title":"Molecular Cell"},{"key":"2026010712103206900_bib31","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/s0168-9525(0002080-1","article-title":"The pachytene checkpoint","volume":"16","author":"Roeder","year":"2000","journal-title":"Trends in Genetics"},{"key":"2026010712103206900_bib32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001062","article-title":"Mouse TRIP13\/PCH2 is required for recombination and normal higher-order chromosome structure during meiosis","volume":"6","author":"Roig","year":"2010","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib33","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/s0092-8674(0080741-2","article-title":"Pch2 links chromatin silencing to meiotic checkpoint control","volume":"97","author":"San-Segundo","year":"1999","journal-title":"Cell"},{"key":"2026010712103206900_bib34","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1007\/s004120050340","article-title":"Localization of SCP2 and SCP3 protein molecules within synaptonemal complexes of the rat","volume":"107","author":"Schalk","year":"1998","journal-title":"Chromosoma"},{"key":"2026010712103206900_bib35","doi-asserted-by":"publisher","first-page":"e1002088","DOI":"10.1371\/journal.pgen.1002088","article-title":"A novel mouse synaptonemal complex protein is essential for loading of central element proteins, recombination, and fertility","volume":"7","author":"Schramm","year":"2011","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib36","doi-asserted-by":"publisher","first-page":"e1001190","DOI":"10.1371\/journal.pgen.1001190","article-title":"Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis","volume":"6","author":"Shin","year":"2010","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib37","doi-asserted-by":"publisher","first-page":"2496","DOI":"10.1093\/emboj\/21.10.2496","article-title":"Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint","volume":"21","author":"Sironi","year":"2002","journal-title":"EMBO Journal"},{"key":"2026010712103206900_bib38","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1038\/ncb3417","article-title":"Meiotic DNA break formation requires the unsynapsed chromosome axis-binding protein IHO1 (CCDC36) in mice","volume":"18","author":"Stanzione","year":"2016","journal-title":"Nature Cell Biology"},{"key":"2026010712103206900_bib39","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/ng1484","article-title":"Silencing of unsynapsed meiotic chromosomes in the mouse","volume":"37","author":"Turner","year":"2005","journal-title":"Nature Genetics"},{"key":"2026010712103206900_bib40","doi-asserted-by":"publisher","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Research"},{"key":"2026010712103206900_bib42","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1093\/nar\/gkx1196","article-title":"Conformational dynamics of the Hop1 HORMA domain reveal a common mechanism with the spindle checkpoint protein Mad2","volume":"46","author":"West","year":"2018","journal-title":"Nucleic Acids Research"},{"key":"2026010712103206900_bib41","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40372","article-title":"A conserved filamentous assembly underlies the structure of the meiotic chromosome axis","volume":"8","author":"West","year":"2019","journal-title":"eLife"},{"key":"2026010712103206900_bib43","doi-asserted-by":"publisher","first-page":"e1000702","DOI":"10.1371\/journal.pgen.1000702","article-title":"Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase","volume":"5","author":"Wojtasz","year":"2009","journal-title":"PLoS Genetics"},{"key":"2026010712103206900_bib44","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1101\/gad.187559.112","article-title":"Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms","volume":"26","author":"Wojtasz","year":"2012","journal-title":"Genes and Development"},{"key":"2026010712103206900_bib45","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1083\/jcb.200603063","article-title":"Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis","volume":"173","author":"Yang","year":"2006","journal-title":"Journal of Cell Biology"},{"key":"2026010712103206900_bib46","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1038\/nprot.2014.134","article-title":"Generating genetically modified mice using CRISPR\/Cas-mediated genome engineering","volume":"9","author":"Yang","year":"2014","journal-title":"Nature Protocols"},{"key":"2026010712103206900_bib47","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.15252\/embj.201797291","article-title":"The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding","volume":"36","author":"Ye","year":"2017","journal-title":"EMBO Journal"},{"key":"2026010712103206900_bib48","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/s1097-2765(0080404-9","article-title":"The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility","volume":"5","author":"Yuan","year":"2000","journal-title":"Molecular Cell"},{"key":"2026010712103206900_bib49","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a016626","article-title":"Recombination, pairing, and synapsis of homologs during meiosis","volume":"7","author":"Zickler","year":"2015","journal-title":"Cold Spring Harbor Perspectives in Biology"}],"container-title":["Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/167\/4\/REP-23-0330.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/rep.bioscientifica.com\/downloadpdf\/journals\/rep\/167\/4\/REP-23-0330.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/167\/4\/e230330\/64910976\/rep-23-0330.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/167\/4\/e230330\/64910976\/rep-23-0330.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:10:37Z","timestamp":1767805837000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/reproduction\/article\/doi\/10.1530\/REP-23-0330\/8217301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,13]]},"references-count":49,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4,1]]}},"URL":"https:\/\/doi.org\/10.1530\/rep-23-0330","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,3,13]]},"published":{"date-parts":[[2024,3,13]]},"article-number":"e230330"}}