Telomere recombination in senescence bypass and meiosis of Saccharomyces cerevisiae
Description
Recombination is an essential component in the scheme of events that maintain telomeric homeostasis. I have been interested in understanding the recombination events that lead to telomere tract maintenance and survival in the budding yeast Saccharomyces cerevisiae. One of the foci of my dissertation has been an investigation of recombination events in cells carrying a novel allele of the multifaceted MRE11 gene. This allele, mre11A470T, confers a variety of phenotypes influencing nuclear telomeres, the most interesting of which is an altered survival in telomerase negative cells. Through an investigation of the genetic dependencies of this phenotype, I found that senescence bypass is mediated by homologous recombination. The analysis of telomere profiles from this allele reveals a unique extended telomere tract phenotype accompanying the amplification of subtelomeric elements. Homeologous recombination and sister chromatid exchange (SCE) between repeats are increased in the absence of Mre11 (19) and Mre11-associated proteins, (144). Our data therefore suggest a model in which mre11A470T generates extended wildtype length telomere tracts through increased homeologous recombination and subsequent break induced replication (BIR) to the end of the chromsosome. (Figure 1.12) BIR is likely to increase viability by increasing the range of telomere tract sizes in telomerase null yeast cells. mre11A470 is invariant among organisms and falls into a highly conserved 13 amino-acid stretch. hsMre11 is associated with alternate lengthening of telomeres (ALT) cancers that use recombination for survival. Our studies may help uncover the role of Mre11 in the regulation of human telomeric recombination in cancers. Elongated telomere tracts in vegetative cells of budding yeast are known to shorten to the size of the majority of telomeres through a one-step recombination process called telomere rapid deletion (TRD) (106) (21). TRD dramatically differs from the slow attrition of telomere tracts observed in the absence of telomerase and has now been found in a multiplicity of organisms suggesting that TRD is part of a common scheme of telomere maintenance among organisms. The second focus of my dissertation is a study of the occurrence and significance of TRD in meiosis. To this end, I calculated the rate of deletions of elongated telomeres in meiosis and investigated its dependency on a key protein regulator of the bouquet assembly, Ndj1. Our results show that meiotic deletions occur at elevated frequencies during meiotic recombination, raising the possibility that TRD may be responsible for the resetting of telomere size during meiosis