Meiosis generates haploid gametes from a diploid cell such that a diploid genome is restored upon fertilization. The proper segregation of chromosomes during the meiotic divisions depends on events in meiotic prophase, such as the pairing and synapsis of homologous chromosomes and crossover recombination. Errors in chromosome segregation are usually fatal to the fertilized zygote but can also result in cancer predisposition or serious developmental disorders. I have identified a meiotic checkpoint that responds to defects in homolog synapsis, independent of a DMA damage/recombination checkpoint, and activates apoptosis to avoid the generation of aneuploid gametes. Not all unsynapsed sequences have the capacity to trigger this checkpoint; rather, this pathway is specifically activated by unsynapsed Pairing Centers (PCs), chromosome sites that promote synapsis in C. elegans. Furthermore, the checkpoint requires the C. elegans homolog of PCH2, a budding yeast pachytene checkpoint gene, suggesting that the molecular mechanism that detects synaptic failure is widely conserved. I plan to further characterize this synapsis checkpoint. I am particularly interested in the PC's contribution to synapsis checkpoint activation. The identification and characterization of proteins that interact with factors required for PC function will provide insight into how this locus activates the checkpoint when unsynapsed. Studies that address the regulation of heterochromatin on unsynapsed chromosomes and how the PC may inhibit the DMA damage checkpoint will also be undertaken. I will determine the role of the synaptonemal complex (SC) in the synapsis checkpoint by characterizing two genes that interact with the SC and appear to be required for the checkpoint by preliminary RNA inteferference (RNAi) experiments. I will investigate the function and regulation of the known checkpoint component, pch-2; a GFP-PCH-2 fusion protein will be localized in a variety of genetic backgrounds as well as provide a reagent to identify interacting proteins biochemically. Furthermore, I will identify additional components of the checkpoint by undertaking an RNAi screen that will focus on candidate genes that fulfill specific expression and phenotypic profile criteria. These complementary approaches will enable me to gain a molecular and mechanistic understanding of how homolog synapsis is monitored and how an unsynapsed or inappropriately synapsed homolog generates a checkpoint signal that is ultimately translated into an apoptotic response. Meiosis produces gametes, such as eggs and sperm. Checkpoints monitor meiotic events to ensure that gametes have the correct number of chromosomes. If a gamete has an incorrect number of chromosomes, the embryo that results from fertilization is often inviable. Occasionally, an embryo inherits an extra chromosome that is not lethal but can cause cancer predisposition or serious developmental defects.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Transition Award (R00)
Project #
4R00RR024110-03
Application #
7626200
Study Section
Special Emphasis Panel (NSS)
Program Officer
Chang, Michael
Project Start
2008-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$249,000
Indirect Cost
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Deshong, Alison J; Ye, Alice L; Lamelza, Piero et al. (2014) A quality control mechanism coordinates meiotic prophase events to promote crossover assurance. PLoS Genet 10:e1004291
Lamelza, Piero; Bhalla, Needhi (2012) Histone methyltransferases MES-4 and MET-1 promote meiotic checkpoint activation in Caenorhabditis elegans. PLoS Genet 8:e1003089
Ye, Alice L; Bhalla, Needhi (2011) Reproductive aging: insights from model organisms. Biochem Soc Trans 39:1770-4
Harper, Nicola C; Rillo, Regina; Jover-Gil, Sara et al. (2011) Pairing centers recruit a Polo-like kinase to orchestrate meiotic chromosome dynamics in C. elegans. Dev Cell 21:934-47
Bhalla, Needhi (2010) Meiotic checkpoints: repair or removal? Curr Biol 20:R1014-6
Bhalla, Needhi; Wynne, David J; Jantsch, Verena et al. (2008) ZHP-3 acts at crossovers to couple meiotic recombination with synaptonemal complex disassembly and bivalent formation in C. elegans. PLoS Genet 4:e1000235