Synaptonemal complex assembly and H3K4Me3 demethylation determine DIDO3 localization in meiosis

We identify a large coiled-coil protein, Sme4/PaMe4, that is highly conserved among the large group of Sordariales and plays central roles in two temporally and functionally distinct aspects of the fungal sexual cycle: first as a component of the meiotic synaptonemal complex (SC) and then, after disappearing and reappearing, as a component of the spindle pole body (SPB). In both cases, the protein mediates spatial juxtaposition of two major structures: linkage of homolog axes through the SC and a change in the SPB from a planar to a bent conformation. Corresponding mutants exhibit defects, respectively, in SC and SPB morphogenesis, with downstream consequences for recombination and astral-microtubule nucleation plus postmeiotic nuclear migration. Sme4 is also required for reorganization of recombination complexes in which Rad51, Mer3, and Msh4 foci relocalize from an on-axis position to a between-axis (on-SC) position concomitant with SC installation. Because involved recombinosome foci represent total recombinational interactions, these dynamics are irrespective of their designation for maturation into cross-overs or noncross-overs. The defined dual roles for Sme4 in two different structures that function at distinct phases of the sexual cycle also provide more functional links and evolutionary dynamics among the nuclear envelope, SPB, and SC. meiosis | pairing | coalignment | postmeiotic division | ascomycetes

Section: Discussionmentioning

confidence: 99%

Sme4 coiled-coil protein mediates synaptonemal complex assembly, recombinosome relocalization, and spindle pole body morphogenesis

Espagne

Vasnier

Storlazzi

et al. 2011

“…The CREST antiserum, recognizing CENP-A, and antibodies to Dido have been described (16,44). We used commercial antibodies to γH2A.X (Millipore and Abcam), phospho-ATM (Rockland), cyclin B1 (BD Biosciences), or α-tubulin (Upstate).…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we used primary cells bearing a mutated death inducer obliterator (Dido) gene. The main product of the Dido gene, Dido3, is a structural protein that localizes to the spindle pole in mitosis (15) and to the synaptonemal complex in meiosis (16). The Dido mutation compromises the spindle metaphase checkpoint, leading to an increased frequency of aberrant anaphases (17).…”

mentioning

confidence: 99%

Centromere-localized breaks indicate the generation of DNA damage by the mitotic spindle

Guerrero

Gamero

Trachana

et al. 2010

Self Cite

Most carcinomas present some form of chromosome instability in combination with spindle defects. Numerical instability is likely caused by spindle aberrations, but the origin of breaks and translocations remains elusive. To determine whether one mechanism can bring about both types of instability, we studied the relationship between DNA damage and spindle defects. Although lacking apparent repair defects, primary Dido mutant cells formed micronuclei containing damaged DNA. The presence of centromeres showed that micronuclei were caused by spindle defects, and cell cycle markers showed that DNA damage was generated during mitosis. Although the micronuclei themselves persisted, the DNA damage within was repaired during S and G2 phases. DNA breaks in Dido mutant cells regularly colocalized with centromeres, which were occasionally distorted. Comparable defects were found in APC mutant cell lines, an independent system for spindle defects. On the basis of these results, we propose a model for break formation in which spindle defects lead to centromere shearing.centrosome | chromosome instability | double-strand break | H2A.X

“…Misregulation of the dido gene is linked to increased incidence of genomic instability, myelodysplasia, and myeloproliferation, melanoma, and infertility (13,17,26,28). Elucidating the mechanisms that govern the complex activities could help clarify the role of Dido in promoting stem cell differentiation, cilia size, tumorigenesis and, as shown here, life expectancy, brain development, and neural behavior alterations.…”

Section: Discussionmentioning

confidence: 99%

“…Dido3 is a key determinant of cilium size (14), and Dido3 mutations cause chromosome segregation defects, meiosis prophase alterations, and stem cell differentiation blockade (17,19,26,27). Misregulation of the dido gene is linked to increased incidence of genomic instability, myelodysplasia, and myeloproliferation, melanoma, and infertility (13,17,26,28).…”

Section: Discussionmentioning

confidence: 99%

Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice

Villares

Gutiérrez

Fütterer

et al. 2015

Self Cite

Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducerobliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sánchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia.ciliopathies | brain patterning | perinatal lethality