Proceedings From Accm19 Cell Cycle Dna Damage Response And Telomeres
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Proceedings From ACCM19: Cell Cycle, DNA Damage Response and Telomeres
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Limiting the DNA Damage Checkpoint Response at Telomeres and DNA Double-strand Breaks
The DNA damage checkpoint responds to both endogenous cell stresses such as replication fork collapse and DNA lesions resulting from exogenous sources such as ionizing-irradiation or exposure to mutagenic chemicals. In response to these stresses, the checkpoint normally arrests or slows down cell division so that repair of DNA damage can occur. Following accurate repair, the cell cycle resumes progression. In this work, I used the budding yeast S. cerevisiae as a model system to examine the mechanisms by which checkpoint activation is alleviated following repair of DNA damage at a defined double-strand DNA break. I also investigated how cells are able to keep the checkpoint system from triggering cell cycle arrest in response to the ends of linear chromosomes, which, in their most basic form, also resemble a double-strand break. I report the identification and characterization of two protein complexes---Pph3-Psy2-Psy4 and KEOPS---that regulate re-entry into the cell cycle following activation of the DNA damage checkpoint, and the integrity of telomeric function, respectively. Pph3-Psy2-Psy4 functions to dephosphorylate histone gamma-H2AX and its mutation results in a hyper-activation of key checkpoint kinases and a prolonged cell-cycle arrest. In contrast, the KEOPS complex functions to promote telomere elongation and single-stranded DNA accumulation following telomere dysfunction. I conclude that cellular viability and genome integrity require the limitation or attenuation of the checkpoint response in both space and time.
Telomeres, DNA Damage Signaling Molecules and Cellular Aging
Normal human cells have a finite life span and undergo senescence after a fixed number of divisions. This process appears to involve some form of genetic memory by which normal cells count the number of divisions they undergo before senescence is reached. The telomere hypothesis proposed that loss of telomeric DNA at the end of human chromosomes acts as a mitotic clock, counting each cell division. Once a critical length of telomeric DNA is reached, senescence is initiated. Questions addressed in this thesis are: (1) How does telomere shortening cause cell cycle exit? (2) Is telomere shortening one of the factors which causes senescence? To address the first question, a model is proposed in chapter two in which telomere shortening is perceived by the cell as DNA damage and that this signal activates a DNA damage signaling pathway leading to senescence. In chapter three, we show that post-translational activation of p53 protein is one factor responsible for upregulation of p21WAF1 in aging cells and PARP (poly (ADP-ribose) polymerase) is involved in the regulation of p53 protein. We found that, either inhibition of PARP or loss of p53 led to extension of life span in normal human fibroblasts. Loss of three genes in our model (PARP, p53 and p21) led to extension of cellular life span. In contrast, loss of ATM gene led to accelerated telomere shortening and premature senescence. We conclude that these DNA damage signaling molecules are involved in regulation of cellular senescence. Answering the second question required reconstitution of telomerase activity in normal human cells. We show in chapter four of this thesis that telomerase activity can be reconstituted in normal cells by forced expression of hTERT, the catalytic subunit of human telomerase. This activity is sufficient to elongate telomeric DNA and extend the replicative life span of cells. These findings provide evidence consistent with the telomere hypothesis and indicate that telomere shortening is one factor which initiates cellular senescence by activation of a DNA damage signaling cascade. Furthermore they indicate that telomere elongation may be sufficient to prevent senescence and render normal human cells immortal.