A novel mammalian HORMA domain-containing protein, HORMAD1, preferentially associates with unsynapsed meiotic chromosomes

Fukuda, Tomoyuki; Daniel, Katrin; Wojtasz, Łukasz; Tóth, Attila; Höög, Christer

doi:10.1016/j.yexcr.2009.08.007

Cited by 126 publications

(155 citation statements)

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“…HORMAD1 coimmunoprecipitates with SYCP3, SYCP2, and AE-bound cohesins, but it does not require SYCP3 to colocalize to aberrant core-like structures that are defective due to lack of SYCP3 (Fukuda et al 2010). Therefore, we conclude that HORMAD1 loss is not sufficient for the phenomena (rescue of Dmc1 or Trip13 mutants by Sycp3 deletion) we observe here.…”

Section: Discussionmentioning

confidence: 58%

“…RAD51 and DMC1 foci in normal meiosis also colocalize to nascent AEs and HORMADs in leptonema (Barlow et al 1997;Wojtasz et al 2009) and actually directly interact with SYCP3 (Tarsounas et al 1999). (Bottom) Localization of SYCP2 is dependent upon SYCP3, so as indicated, loss of SYCP3 results in aberrant pseudoaxial elements, or cores, consisting only of cohesin proteins such as REC8, SMC1b, and STAG3 (Pelttari et al 2001;Fukuda et al 2010). In our model, the disrupted AE structure caused by SYCP2/SYCP3 absence, which also causes discontinuities in the cohesin complex (dashed red line) allows the RAD51-bound DSB ends (depicted here in Dmc1 mutants) to have unimpeded access to the sister and will recombine in a RAD54-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

“…Important similarities are that essential components of the IH bias/ barrier to sister chromatid recombination in yeast are axial element proteins (Red1, Mek1, and Hop1), as are SYCP3 and SYCP2 in mice (our data), as well as the cohesin Rec8. Mice have two Hop1 orthologs, HORMAD1 and HORMAD2, that become colocalized to nascent AEs ("cores") during leptonema and are removed upon synapsis, consistent with a role conserved with Hop1 and/or Red1 (Wojtasz et al 2009;Fukuda et al 2010). Additionally, Hormad1 mutants have decreased DSB levels as do hop1 yeast (Shin et al 2010), but it is not known whether Hormad1 has a role in partner choice.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Evidence That Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice

Bolcun-Filas

Schimenti

2011

Genetics

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Chiasmata resulting from interhomolog recombination are critical for proper chromosome segregation at meiotic metaphase I, thus preventing aneuploidy and consequent deleterious effects. Recombination in meiosis is driven by programmed induction of double strand breaks (DSBs), and the repair of these breaks occurs primarily by recombination between homologous chromosomes, not sister chromatids. Almost nothing is known about the basis for recombination partner choice in mammals. We addressed this problem using a genetic approach. Since meiotic recombination is coupled with synaptonemal complex (SC) morphogenesis, we explored the role of axial elements -precursors to the lateral element in the mature SC -in recombination partner choice, DSB repair pathways, and checkpoint control. Female mice lacking the SC axial element protein SYCP3 produce viable, but often aneuploid, oocytes. We describe genetic studies indicating that while DSB-containing Sycp3 2/2 oocytes can be eliminated efficiently, those that survive have completed repair before the execution of an intact DNA damage checkpoint. We find that the requirement for DMC1 and TRIP13, proteins normally essential for recombination repair of meiotic DSBs, is substantially bypassed in Sycp3 and Sycp2 mutants. This bypass requires RAD54, a functionally conserved protein that promotes intersister recombination in yeast meiosis and mammalian mitotic cells. Immunocytological and genetic studies indicated that the bypass in Sycp3 2/2 Dmc1 2/2 oocytes was linked to increased DSB repair. These experiments lead us to hypothesize that axial elements mediate the activities of recombination proteins to favor interhomolog, rather than intersister recombinational repair of genetically programmed DSBs in mice. The elimination of this activity in SYCP3-or SYCP2-deficient oocytes may underlie the aneuploidy in derivative mouse embryos and spontaneous abortions in women.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Genetic Evidence That Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice

Bolcun-Filas

Schimenti

2011

Genetics

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“…We and others have identified two meiosis-specific HORMA (Hop1, Rev7, and Mad2) domain proteins, HORMAD1 and HORMAD2, that preferentially localize to unsynapsed chromosome axes in mice in both sexes (Wojtasz et al 2009;Fukuda et al 2010;Shin et al 2010). HORMAD1 ensures that sufficient numbers of unrepaired DSBs are available for homology search (Shin et al 2010;Daniel et al 2011) and promotes SC formation independent of its role in homology search (Daniel et al 2011).…”

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confidence: 99%

Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms

Wojtasz¹,

Cloutier²,

Baumann³

et al. 2012

Genes Dev.

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142

162

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Meiotic crossover formation involves the repair of programmed DNA double-strand breaks (DSBs) and synaptonemal complex (SC) formation. Completion of these processes must precede the meiotic divisions in order to avoid chromosome abnormalities in gametes. Enduring key questions in meiosis have been how meiotic progression and crossover formation are coordinated, whether inappropriate asynapsis is monitored, and whether asynapsis elicits prophase arrest via mechanisms that are distinct from the surveillance of unrepaired DNA DSBs. We disrupted the meiosis-specific mouse HORMAD2 (Hop1, Rev7, and Mad2 domain 2) protein, which preferentially associates with unsynapsed chromosome axes. We show that HORMAD2 is required for the accumulation of the checkpoint kinase ATR along unsynapsed axes, but not at DNA DSBs or on DNA DSBassociated chromatin loops. Consistent with the hypothesis that ATR activity on chromatin plays important roles in the quality control of meiotic prophase, HORMAD2 is required for the elimination of the asynaptic Spo11 -/-, but not the asynaptic and DSB repair-defective Dmc1 -/-oocytes. Our observations strongly suggest that HORMAD2-dependent recruitment of ATR to unsynapsed chromosome axes constitutes a mechanism for the surveillance of asynapsis. Thus, we provide convincing evidence for the existence of a distinct asynapsis surveillance mechanism that safeguards the ploidy of the mammalian germline.[Keywords: asynapsis surveillance; meiotic prophase checkpoint; ATR; HORMA domain; meiosis; aneuploidy] Supplemental material is available for this article. Received January 30, 2012; revised version accepted March 19, 2012. Orderly chromosome segregation during the first meiotic division requires that homologous maternal and paternal chromosomes (called homologs) become physically linked, thereby forming so-called bivalents during the first meiotic prophase (Page and Hawley 2003). In most organisms, including mammals, meiotic recombination generates reciprocal exchanges, called crossovers (COs), between homologous DNA sequences. Interhomolog COs and sister chromatid cohesion together form the basis of the physical linkages, called chiasmata, that connect pairs of homologs during the first meiotic metaphase. Therefore, at least one CO must form between each pair of homologs to ensure correct segregation during the first meiotic division.CO formation requires that homologs find each other. To achieve this, double-strand breaks (DSBs) are actively introduced into the genome at the beginning of prophase by the SPO11 enzyme (Keeney et al. 1997;Baudat et al. 2000;Romanienko and Camerini-Otero 2000). This is followed by the resection of DSB ends, which creates 39 ssDNA overhangs (Neale et al. 2005). The RAD51 and DMC1 recombinases bind single-stranded DSB ends and assist homology search through promoting strand invasion of resected DSB ends into homologous DNA sequences (Baudat and de Massy 2007). Several DSB ends work in parallel on each pair of homologs to ensure alignment along the full lengths of homolo...

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“…It is recognized that HORMA‐domain containing proteins (HORMAD) plays a crucial role in the regulation of cell cycle and in mitosis and meiosis 27, 28, 29. HORMADs (HORMAD1 and HORMAD2) share homology with the meiosis‐specific HORMA‐domain proteins, which are conserved in various organisms 16…”

Section: Discussionmentioning

confidence: 99%

HORMAD2 methylation‐mediated epigenetic regulation of gene expression in thyroid cancer

Lin

Hou

Guan

et al. 2018

J Cellular Molecular Medi

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This study is aimed to investigate the methylation level of candidate genes and its impact on thyroid carcinoma (THCA) development. Infinium Human Methylation 450 BeadChip Arrays by Illumina (Illumina HM450K) was the most popular CpG microarray platform widely used in biological and medical research. The methylation level of differentially expressed genes and their corresponding CpG sites were analysed by R programme. The expression of HORMAD2 was evaluated by qRT‐PCR and Western blot, while the methylation level was examined via methylation‐specific PCR. Cell viability, metastasis, cell cycle and apoptosis were detected by MTT assay, transwell and wound healing assay and flow cytometry, respectively, after treatment with 5‐aza‐2′‐deoxycytidine (5‐Aza). Tumour formation assay was used to analyse thyroid tumour growth in nude mice in vivo. The methylation levels of all 116 differentially expressed genes were analysed. HORMAD2 was significantly hypermethylated and its mRNA expression was inhibited in THCA cells. After treatment with 5‐Aza, HORMAD2 expression was up‐regulated in THCA cells and its overexpression can suppress thyroid cancer cell viability, mobility and invasiveness remarkably. Up‐regulation of HORMAD2 in THCA cells could prolong G0/G1 phase and shorten S phase to impede cell mitosis as well as promote thyroid cancer cells apoptosis. Furthermore, tumour formation assay showed that increased HORMAD2 level impeded tumour growth in vivo. Hypermethylation of HORMAD2 could induce THCA progression, while hypomethylation of HORMAD2 retard cell growth and mobility and facilitate apoptosis through increasing its mRNA expression.

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A novel mammalian HORMA domain-containing protein, HORMAD1, preferentially associates with unsynapsed meiotic chromosomes

Cited by 126 publications

References 51 publications

Genetic Evidence That Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice

Genetic Evidence That Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice

Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms

HORMAD2 methylation‐mediated epigenetic regulation of gene expression in thyroid cancer

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