We investigate the ways in which homologous chromosomes communicate with one another, via recombination and recombination-mediated whole chromosome pairing during meiosis. Recombination is studied in budding yeast with respect to the processes that ensure occurrence of interactions between homologous chromosomes, rather than between sisters as during mitotic recombination, and with respect to the nature of homology searching by an initiating double-strand break (DSB). Recombination- mediated whole chromosome pairing is studied in the filamentous fungus Sordaria. Our studies will address the possibilities of long-range contacts, per-chromosome pairing, interference/communication among developing interhomolog interactions and the roles and interactions among dynamic movement and recombinosome-mediated effects during the resolution of chromosomal entanglements that arise during pairing. We will also determine the molecular natures of genetically-identified DSB/early recombination proteins in this organism. We also investigate how chromosomal events can occur in an evenly-spaced pattern without direct genetic specification of position, using as a model system the patterning of crossover (CO) recombination events along meiotic chromosomes. We will further investigate specific issues in this field by quantitative modeling. We will continue our analysis of CO patterning in wild type and mutant strains of budding yeast and phenotypic and biochemical analysis of the roles of specific molecules of interest. We will also explore how chromatin expansion/contraction status varies globally, in temporal correlation with meiotic stages, and locally, in spatial relation to positions of CO sites. This analysis will include studies of mutants of interest in budding yeast and isolation and characterization of new relevant mutants in Sordaria. Finally, we study recombination-independent homologous pairing, a process whose mechanistic basis remains an important mystery. We will analyze our recently-described in vitro DNA/DNA pairing process. In parallel, we will further examine pairing in vivo in budding yeast. We will also further investigate a phenomenon of filamentous fungus Neurospora that appears to involve direct DNA/DNA pairing.

Public Health Relevance

Meiosis is the specialized cellular program that yields gametes for sexual reproduction. Interactions between homologous chromosomes lie at the heart of the meiotic program and our research addresses three aspects of this inter-homolog interaction program. Certain defects in this program result in chromosome mis-segregation, which, in turn, accounts for many important genetic diseases. Other defects result in sterility. Advances in fundamental understanding of meiotic inter-homolog interactions will ultimately have implications for diagnosis and, hopefully treatment of diverse reproductive defects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics C Study Section (MGC)
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Reddy, Michael K
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Harvard University
Schools of Arts and Sciences
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Mirkin, Ekaterina V; Chang, Frederick S; Kleckner, Nancy (2014) Protein-mediated chromosome pairing of repetitive arrays. J Mol Biol 426:550-7
Zhang, Liangran; Liang, Zhangyi; Hutchinson, John et al. (2014) Crossover patterning by the beam-film model: analysis and implications. PLoS Genet 10:e1004042
Zhang, Liangran; Wang, Shunxin; Yin, Shen et al. (2014) Topoisomerase II mediates meiotic crossover interference. Nature 511:551-6
De Muyt, Arnaud; Zhang, Liangran; Piolot, Tristan et al. (2014) E3 ligase Hei10: a multifaceted structure-based signaling molecule with roles within and beyond meiosis. Genes Dev 28:1111-23
Gladyshev, Eugene; Kleckner, Nancy (2014) Direct recognition of homology between double helices of DNA in Neurospora crassa. Nat Commun 5:3509
Fisher, Jay K; Bourniquel, Aude; Witz, Guillaume et al. (2013) Four-dimensional imaging of E. coli nucleoid organization and dynamics in living cells. Cell 153:882-95
Mirkin, Ekaterina V; Chang, Frederick S; Kleckner, Nancy (2013) Dynamic trans interactions in yeast chromosomes. PLoS One 8:e75895
Conover, Alyson J; Danilowicz, Claudia; Gunaratne, Ruwan et al. (2011) Changes in the tension in dsDNA alter the conformation of RecA bound to dsDNA-RecA filaments. Nucleic Acids Res 39:8833-43
Feinstein, Efraim; Danilowicz, Claudia; Conover, Alyson et al. (2011) Single-molecule studies of the stringency factors and rates governing the polymerization of RecA on double-stranded DNA. Nucleic Acids Res 39:3781-91
Koszul, Romain; Kleckner, Nancy (2009) Dynamic chromosome movements during meiosis: a way to eliminate unwanted connections? Trends Cell Biol 19:716-24

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