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Control del inicio de la recombinación meiótica

The World Health Organization (WHO) considers infertility as a disease ( WHO definition), and estimates 1-2% of prevalence in couples in developed countries (3.6 million of infertile couples in high-income regions) (Mascarenhas et al., 2010). A key feature of meiosis, the cellular program that generates gametes, is the recombination between homologous chromosomes (maternal and paternal) that, in addition to generate genetic diversity, facilitates accurate chromosome segregation. Defects in chromosome segregation during meiosis cause miscarriages, infertility and genetic diseases, and reveal the important to understand the meiotic recombination process.

Our laboratory is interested in how this particular recombination is regulated. To this aim we are using the fission yeast Schizosaccharomyces pombe, since this organism is a proven model system for different eukaryotic conserved processes.

In particular we are studying how linear elements (LinEs) -dynamic chromosome structures similar to the synaptonemal complex of other eukaryotes-, and the conserved pre-recombination complexes (SFT and DSBC-complexes) are regulated to generate the DNA double-strand breaks (DSBs) required for the initiation of the recombination process. Our work in collaboration with Dr. Smith at the Fred Hutchinson Cancer Research Center (Seattle, USA) has identified several components of LinEs (Martín-Castellanos et al., 2005; Davis et al., 2008; Ma et al., 2017). LinE-components are specifically enriched at the recombination hotspots (genome sequences where DSB occurs), and their binding is proportional to the strength of the hotspot, suggesting they function as determinants for DSB formation (Fowler et al., 2013; Martín-Castellanos et al., 2013). In addition, we have studied functional relationships among different components and identified key protein residues required for complex organization/localization and DSB formation (Ma et al., 2017). LinEs serve as platforms where the pre-recombination complexes, which eventually will generate the breaks in the DNA, are loaded. Our work has also identified a component of these complexes, increasing our knowledge about the functional organization of the SFT-complex (Martín-Castellanos et al., 2005; Bonfils et al., 2011).

A strict regulation of DSB formation during meiosis is critical to maintain the genome stability during this physiological situation, in which self-inflicted DNA damage is used as a source of genetic recombination. Thus, DNA break formation has to be coordinated with meiotic progression and, indeed, the S-phase checkpoint blocks DSB formation during meiotic DNA replication both in fission and budding yeast. Apart from this coordination this aspect of meiosis is largely unknown in most species. Recently, we have found that CDK (cyclin-dependent kinase) activity, which controls meiotic progression, also regulates DSB formation in fission yeast (Bustamante-Jaramillo et al. 2019). Maturation of LinEs seems to be an important point of CDK regulation, modulating the binding to chromatin of one of their structural components. Furthermore, CDK activity might also control downstream events balancing the repair pathways after DSB formation. Therefore, CDK activity in meiosis may regulate different steps of the recombination process.

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Figure.Cytological localization of proteins required for the initiation of meiotic recombination, genome localization of LinE-components, physical analysis of DSB formation, and genetic analysis of recombination.

Red Meiosis
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Miembros del grupo

Cristina Martín Castellanos Científico Titular (CSIC)
ORCID: 0000-0002-1303-2517
ResearcherID: F-4502-2017
Inés Palacios Blanco Estudiante de Máster
Lucía Gómez Suárez Técnico

Contacto

Cristina Martín Castellanos cmartin@usal.es
923294924
Laboratorio 2.11

Publicaciones recientes

Bustamante-Jaramillo LF, Ramos C, Alonso L, Sesmero A, Segurado M, Martín-Castellanos C (2019)
CDK contribution to DSB formation and recombination in fission yeast meiosis.
PLoS Genetics. 15(1):e1007876
doi: 10.1371/journal.pgen.1007876
Ma L, Fowler KR, Martín-Castellanos C, Smith GR (2017)
Functional organization of protein determinants of meiotic DNA break hotspots
Scientific Reports 7:1393
doi:10.1038/s41598-017-00742-3
Martín-Castellanos C, Fowler KR and Smith GR (2013)
Making chromosomes hot for breakage
Cell Cycle 12: 1327-1328
doi:10.4161/cc.24576
Fowler KR, Gutiérrez-Velasco S, Martín-Castellanos C and Smith GR (2013)
Protein determinants of meiotic DNA break hotspots
Mol. Cell 49: 983-996
doi: 10.1016/j.molcel.2013.01.008
Bonfils S, Rozalén AE, Smith GR, Moreno S and Martín-Castellanos C (2011)
Functional interactions of Rec24, the fission yeast ortholog of mouse Mei4, with the meiotic recombination-initiation complex
J. Cell Sci. 124: 1328-1338
doi:10.1242/jcs.079194
Davis L, Rozalén AE, Moreno S, Smith G and Martín-Castellanos C (2008)
Rec25 and Rec27, novel linear-element components, link cohesin to meiotic DNA breakage and recombination
Curr. Biol. 18: 849-854
doi: 10.1016/j.cub.2008.05.025

Proyectos de investigación

MINECO (BFU2013-45182-P)
MINECO: Biología Funcional de la Red Meiótica, MEIONet (Acciones de Dinamización «Redes de Excelencia ») (BFU2015-71786-REDT)
Junta de Castilla y León: CSI084U16
Unidad de Investigación Consolidada de Castilla y León: UIC 028