Meiosis is a specialized cell division process that results in the formation of haploid gametes (i.e.: eggs and sperm) and is therefore essential for sexual reproduction and generating genetic diversity. The reduction of the chromosome complement by half is accomplished by following a single round of DNA replication with two consecutive rounds of chromosome segregation (meiosis I and meiosis II). Achieving accurate chromosome segregation is paramount for the successful formation of haploid gametes. To segregate properly, chromosomes must undergo a series of steps that are unique to meiosis I, including: (1) homologous pairing, (2) formation of a """"""""zipper-like"""""""" structure (the synaptonemal complex or SC) between aligned homologs, and (3) completion of meiotic recombination leading to physical attachments (chiasmata) between homologs. Significantly, errors in any of these steps lead to chromosome nondisjunction, with disastrous consequences including miscarriages and birth defects such as Down syndrome. Our goal is to investigate the roles, macromolecular assembly and regulation of the SC, whose functions are poorly understood and a matter of much debate despite its ubiquitous presence from yeast to humans. Focusing on this goal will reveal how synapsis intersects with the regulation of meiotic progression and promotes accurate chromosome segregation. We are addressing this important issue by studying it in the nematode C. elegans, an ideal model system for meiotic studies, amenable to various genetic, molecular, biochemical and cytological approaches. We have recently identified four critical SC components (SYP-1, SYP-2, SYP-3 and SYP-4), proteins that regulate SC assembly (CRA-1), meiotic recombination (HIM-18), and SC disassembly and sister chromatid cohesion during meiosis I (LAB-1). Beginning with the analysis of the molecular mechanisms through which several of these proteins function during meiosis, we propose to address the fundamental issues of how pairing, synapsis and recombination intersect and are regulated resulting in accurate chromosome segregation. We will do this by combining cytological observations done in the context of an intact 3-D nuclear architecture in this system, with results from molecular, genetic and biochemical approaches. Taken together, this application will provide significant new insights into the molecular mechanisms underlying accurate meiotic chromosome segregation and move us forward in our understanding of analogous processes in higher eukaryotes.
Meiosis is a specialized cell division program required for the production of eggs and sperm and therefore essential for human reproduction. Errors during meiosis are predicted to account for approximately 35% of all miscarriages in humans and birth defects such as Down syndrome. The proposed research will investigate the molecular mechanisms promoting accurate meiotic chromosome segregation thereby laying the foundation for the development of effective preventive strategies.
|Gao, Jinmin; Colaiácovo, Monica P (2017) Zipping and Unzipping: Protein Modifications Regulating Synaptonemal Complex Dynamics. Trends Genet :|
|Nottke, Amanda C; Kim, Hyun-Min; Colaiácovo, Monica P (2017) Wrestling with Chromosomes: The Roles of SUMO During Meiosis. Adv Exp Med Biol 963:185-196|
|Nadarajan, Saravanapriah; Lambert, Talley J; Altendorfer, Elisabeth et al. (2017) Polo-like kinase-dependent phosphorylation of the synaptonemal complex protein SYP-4 regulates double-strand break formation through a negative feedback loop. Elife 6:|
|Nadarajan, Saravanapriah; Mohideen, Firaz; Tzur, Yonatan B et al. (2016) The MAP kinase pathway coordinates crossover designation with disassembly of synaptonemal complex proteins during meiosis. Elife 5:e12039|
|Gao, Jinmin; Barroso, Consuelo; Zhang, Pan et al. (2016) N-terminal acetylation promotes synaptonemal complex assembly in C. elegans. Genes Dev 30:2404-2416|
|Kim, Hyun-Min; Colaiácovo, Monica P (2016) CRISPR-Cas9-Guided Genome Engineering in C. elegans. Curr Protoc Mol Biol 115:31.7.1-31.7.18|
|Kim, Hyun-Min; Colaiácovo, Monica P (2015) New Insights into the Post-Translational Regulation of DNA Damage Response and Double-Strand Break Repair in Caenorhabditis elegans. Genetics 200:495-504|
|Mendes, Tasha K; Novakovic, Stevan; Raymant, Greta et al. (2015) Investigating the role of RIO protein kinases in Caenorhabditis elegans. PLoS One 10:e0117444|
|Norris, Adam D; Kim, Hyun-Min; Colaiácovo, Mónica P et al. (2015) Efficient Genome Editing in Caenorhabditis elegans with a Toolkit of Dual-Marker Selection Cassettes. Genetics 201:449-58|
|Kim, Hyun-Min; Colaiácovo, Monica P (2015) DNA Damage Sensitivity Assays in Caenorhabditis elegans. Bio Protoc 5:|
Showing the most recent 10 out of 39 publications