TY - JOUR TI - Checkpoint-mediated regulations of meiotic double-strand-break repair and crossover formation in Drosophila melanogaster DO - https://doi.org/doi:10.7282/T35H7GBR PY - 2010 AB - During meiotic prophase, programmed DNA double-strand breaks (DSBs) are required to initiate recombination between homologous chromosomes and are repaired as either crossovers or noncrossovers. Crossovers provide a link between the homologs and facilitate their orientation on the meiosis I spindle and segregation at anaphase. Although studies in a variety of experiment systems have identified and characterized numerous factors necessary for crossover formation, far less is known about how the distribution and number of crossovers are controlled. The process of repairing meiotic DSBs is monitored by at least two surveillance mechanisms: the canonical DSB repair checkpoint that responds to DNA damage and another that requires the widely conserved AAA+ ATPase Pch2, hereafter referred to as the "pachytene checkpoint." In Saccharomyces cerevisiae and Caenorhabditis elegans, pachytene checkpoint activity has been detected with mutations in genes encoding structural proteins required for crossing over; however, it remains unclear what the underlying process is that the pachytene checkpoint is monitoring. I identified the Drosophila pachytene checkpoint by conducting a phenotypic analysis of different classes of recombination-defective mutants. Specifically, the Drosophila pachytene checkpoint delays prophase progression when genes necessary for DSB repair and crossover formation are defective, but surprisingly functions independently of DSB formation. In addition, I investigated the relationship between chromosome structure and the pachytene checkpoint and found that defects in chromosome axis components also cause pch2-dependent delays. These findings suggest the pachytene checkpoint monitors two genetically distinct events: an early function of DSB repair proteins and the organization of chromosome axes. In support of this model, heterozygous chromosome aberrations result in a pachytene delay and interchromosomal increase in crossovers that are both dependent on pch2. My studies have led to a model where the sites and/or conditions required to promote crossovers are established independent of DSB formation early in meiotic prophase. The pachytene checkpoint may function to promote an optimal number of crossovers by regulating the duration of PCH2 expression, which defines the crossover determination phase. These results have provided new insights into this highly conserved surveillance mechanism as well as its relationship to pachytene progression and crossover control. KW - Microbiology and Molecular Genetics KW - Meiosis KW - Drosophila melanogaster--Genetics KW - Genetic recombination--Research LA - eng ER -