All sexually reproducing organisms rely on the events of meiosis, the cell division that produces gametes such as sperm and eggs. In order to ensure a proper chromosome complement in successive generations and to promote genetic diversity, meiotic chromosomes will align with their counterparts, synapse, and undergo recombination, the means of genetic exchange. Failure to accurately complete these steps during meiosis results in devastating consequences for progeny.
The mechanisms that execute and monitor the genetic interactions in meiosis are an exciting area of study in the field. In particular, understanding the importance of chromatin localization and dissecting the interactions of chromatin and various associated meiotic proteins are critical to our understanding of meiosis. Additionally, checkpoints exist that monitor proper completion of meiotic events, but the control of these checkpoints is not fully understood.
Using a variety of cytological and genetic techniques in C. elegans, the work here addresses the importance of perinuclear localization of chromatin during meiosis. A class of nuclear membrane-associated proteins called the LEM proteins are involved in perinuclear tethering of chromatin. The three LEM proteins in C. elegans have differential effects on meiotic fidelity. Loss of one of these proteins, LEM-2, causes impaired repair and processing of double-stranded DNA breaks, which are necessary for recombination. It also induces meiotic errors that result in elevated levels of cell death in the germline. Loss of another one of these proteins, EMR-1, also affects meiotic DNA repair but less severely than LEM-2. Finally, LEM-3 appears to be required for a meiotic checkpoint that monitors synapsis.
This thesis also provides insight into the regulatory mechanisms that trigger germ cell death when errors in meiosis activate checkpoints. A conserved pro-apoptotic protein, EGL-1, is necessary for the two checkpoints to induce apoptosis, but its requirement for each checkpoint depends on the manner in which they are activated. Experiments also reveal that CED-13, a largely uncharacterized protein with homology to EGL-1, also has a role in meiotic checkpoints. Moreover, my studies indicate that recombination negatively regulates egl-1 mediated germline apoptosis, potentially as a mechanism to promote repair over removal of defective meiotic nuclei.