Checkpoint proteins outside the cell cycle: Roles in postmitotic neurons and meiosis.

摘要

Maintaining the integrity of the genetic code is of paramount importance to the health and reproduction of organisms. Checkpoints, the mechanisms by which cells detect damage to DNA and halt cell cycle progression until repair is complete, are essential to the maintenance of genomic stability. For the first part of my doctoral research, I examined the transcriptional consequences of the loss of the conserved DNA damage checkpoint protein ATM (Ataxia-telangiectasia mutated) in the adult murine brain. Although patients with A-T suffer from neuronal abnormalities, I was unable to identify consistent differential expression in Atm -/- mouse brain at baseline or in response to an excitotoxic stress paradigm, suggesting that neurological defects in the mouse model of A-T do not manifest at a transcriptional level. For the second part of my doctoral research, I characterized the role of conserved checkpoint proteins in meiosis, a specialized cell differentiation cycle, in the fission yeast Schizosaccharomyces pombe. My results suggest that DNA damage during meiotic S-phase becomes a substrate for meiotic recombination without activating a canonical damage checkpoint response. Further, damage repair in fission yeast meiosis may also escape monitoring by the recombination checkpoint, which responds to defects in the repair of programmed double-strand breaks. In contrast to programmed meiotic damage, induced meiotic damage may be preferentially repaired by sister chromatid recombination. In addition, the kinetics of meiotic damage repair may be influenced by the presence of homologous chromosomes.