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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044794-23
Application #
8301552
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Reddy, Michael K
Project Start
1990-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
23
Fiscal Year
2012
Total Cost
$754,820
Indirect Cost
$281,114
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Kleckner, Nancy (2016) Questions and Assays. Genetics 204:1343-1349
Gladyshev, Eugene; Kleckner, Nancy (2016) Recombination-Independent Recognition of DNA Homology for Repeat-Induced Point Mutation (RIP) Is Modulated by the Underlying Nucleotide Sequence. PLoS Genet 12:e1006015
Zickler, Denise; Kleckner, Nancy (2016) A few of our favorite things: Pairing, the bouquet, crossover interference and evolution of meiosis. Semin Cell Dev Biol 54:135-48
Yoon, Sang-Wook; Lee, Min-Su; Xaver, Martin et al. (2016) Meiotic prophase roles of Rec8 in crossover recombination and chromosome structure. Nucleic Acids Res 44:9296-9314
Bomblies, Kirsten; Jones, Gareth; Franklin, Chris et al. (2016) The challenge of evolving stable polyploidy: could an increase in "crossover interference distance" play a central role? Chromosoma 125:287-300
Gladyshev, Eugene; Kleckner, Nancy (2016) Recombination-independent recognition of DNA homology for repeat-induced point mutation. Curr Genet :
Zickler, Denise; Kleckner, Nancy (2015) Recombination, Pairing, and Synapsis of Homologs during Meiosis. Cold Spring Harb Perspect Biol 7:
Wang, Shunxin; Zickler, Denise; Kleckner, Nancy et al. (2015) Meiotic crossover patterns: obligatory crossover, interference and homeostasis in a single process. Cell Cycle 14:305-14
Gladyshev, Eugene; Kleckner, Nancy (2014) Direct recognition of homology between double helices of DNA in Neurospora crassa. Nat Commun 5:3509
Mirkin, Ekaterina V; Chang, Frederick S; Kleckner, Nancy (2014) Protein-mediated chromosome pairing of repetitive arrays. J Mol Biol 426:550-7

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