Academic Ageing Seminar - The determinants of DNA degradation at uncapped telomeres
Location: Seminar Room, Wolfson Research Centre, Campus for Ageing and Vitality
Time/Date: 25th February 2010, 12:30 - 13:30
You are invited to attend the Academic Ageing Seminar on Thursday 25 February 2010 in the Wolfson Seminar Room, Institute for Ageing and Health. The seminar will take place at 12.30 pm with sandwiches available from 12 noon.
The speaker is James Dewar, IAH PhD Student and the title of his talk is 'The determinants of DNA degradation at uncapped telomeres'
Abstract:
From budding yeast to humans, the DNA of eukaryotes is distributed across linear chromosomes. The DNA at the end of each chromosome resembles one half of a DNA double strand break, which is readily recognized and processed by the cell’s DNA Damage Response (DDR). Telomeres are nucleoprotein caps at the end of most eukaryotic chromosomes, which shield the chromosome ends from recognition and processing by the DDR and ‘cap’ the telomere. Inactivation of specific protein components of the telomere cap (Cdc13 in budding yeast, POT1 in humans) renders the telomeres ‘uncapped’.
At uncapped telomeres in humans and yeast, Exo1 and other unknown nucleases degrade the telomeric DNA, stimulating a potent cell cycle arrest and leading to cell death. This process is believed to play a causal role in mammalian ageing, as Exo1 activity at dysfunctional telomeres has been shown to be partially responsible for the premature ageing seen in telomerase knock-out mice with critically short telomeres.
To identify novel determinants of ageing, we wanted to identify the hereto-unknown nuclease(s) at uncapped telomeres. We used budding yeast as a model eukaryotic organism to identify the nuclease activities that occur following telomere uncapping due to inactivation of Cdc13.
We find that Pif1 – a helicase, conserved from yeast to humans – is required for degradation of telomeric DNA in a parallel pathway to Exo1. Together, Pif1 and Exo1 determine degradation of uncapped telomeres. Elimination of the Pif1- and Exo1-dependent nuclease activities prevents Cdc13-defective dysfunctional telomeres stimulating a DDR or inducing senescence. These data suggest that PIF1 may be a determinant of mammalian ageing, acting in synergy with EXO1.
Published: 3rd February 2010
