A role for nuclear actin filaments at damaged telomeres

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DESCRIPTION (provided by applicant): Actin is among the most well characterized proteins in eukaryotic organisms and is required for many cytosolic processes, including cell motility, intracellular transport and the structural integrity of the cell. Recent reports have suggested that actin also participates in a range of nuclear processes in numerous cell types, though the role of this nuclear pool of actin is largely unknown. Previous work on nuclear actin has been limited due to the difficulty associated with visualizing actin in intact somatic nuclei. I have recently developed novel reporters of both monomeric and filamentous pools of nuclear actin in live cells. Using these tools in collaboration with the Blackburn lab, we have made the exciting discovery that actin filaments colocalize with uncapped telomeres. To investigate the role of telomeric actin, I propose to determine the live cell dynamics of nuclear actin with respect to both capped and deprotected telomeres. I will also investigate whether the association is dependent on the DNA damage response, as well as factors responsible for recruitment and regulation of telomeric actin. PUBLIC HEALTH RELEVANCE: Decades of experimental research on telomere biology have provided a clear link between telomere function and aging. Disruption or loss of active telomerase has been shown to cause telomeres to shorten and trigger cellular senescence, both in vivo and in vitro (Yu et al. 1990, Harley et al. 1990). When active telomerase is introduced into cell cultures with low telomerase activity, telomeres lengthen and the cells can become immortalized (Bodnar et al. 1998, Counter et al. 1998). From these observations, the traditional view that emerged was that the loss of telomere "critical length" promotes senescence. However, more recent evidence suggests that rather than telomere length per se, it is the loss of protection ("uncapping") of the telomere that results from telomere shortening that limits cell proliferation (Blackburn 2000). The proposed research identifies nuclear actin as a novel factor present at uncapped telomeres, and investigates potential roles for telomeric actin in signaling to the machineries involved in cell cycle exit, apoptosis and genomic instability. This research will provide insight into the consequences of uncapped telomeres that are responsible for promoting cellular senescence.