Saccharomyces THO components affect telomere functions through two mechanistically different pathways

• Main Authors: Tai-Yuan Yu, 尤泰元
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/20193494067098045652

博士 === 國立陽明大學 === 生物藥學研究所 === 101 === The THO (suppressor of the Transcriptional defects of Hpr1 mutants by Overexpression) complex is a general transcription elongation factor. There are four protein components, Tho2p, Hpr1p, Mft1p, and Thp2p in the THO complex. Deletion of tho2 or hpr1 caused telomere lengthening by ~50-100 bps and enhanced the telomere silencing effect. Since mutations in THO complex components markedly decrease the amount of long transcripts, we concluded that THO2 or HPR1 regulates telomere length and silencing effect through reducing the expression of a large-sized telomere associated protein, Rif1p. Independent to reducing the expression of Rif1p, we also found that mutations in THO complex components THO2 and HPR1 in telomerase deficiency cells caused accelerated senescence and telomere recombination which were not through accelerated telomere shortening. The acceleration of senescence and telomere recombination in THO mutants was also transcription- dependent and co-appeared with decreasing telomere transcripts and accumulation of DNA:RNA hybrid at telomeres. The early senescence and telomere recombination phenotype could be reverted by deletion of hrs1 (component of RNA pol II mediator complex), over-expression of SUB2 (interacting with THO to form TREX complex) or RNH1 (digest RNA of DNA:RNA hybrid). We concluded that these co-transcriptional stalled telomeric DNA: RNA hybrids induced premature senescence by activating DNA damage checkpoint Rad53p phosorylation and recruited recombination repair factors Rad51p and Rad52p to form telomere recombination bypassing senescence in tho mutants. Together our results indicated that components of THO complex affect telomeres through two mechanistically different pathways.