Christine T Parusel et al. (2005) International Worm Meeting "Suppression of DNA damage-induced cell cycle arrest and apoptosis by C. elegans URI-1"

Christine T Parusel, Michael O Hengartner, Wilhelm Krek, Monica Gotta, Ekat A Kritikou

[International Worm Meeting, 2005]

URI is an evolutionary conserved unconventional member of the prefoldin family of molecular chaperones that, at the biochemical and biological level, is multifunctional. It interacts with several partner proteins with key roles in transcriptional control including the RPB5 core subunit of RNA pol II and the TIP49/TIP48 ATPases, components of various chromatin remodeling complexes. More recently, URI has also been shown to interact with the parathyroid tumor suppressor parafibromin, a component of the PAF1 complex involved in histone methylation and cell cycle control. Notably, there is evidence from functional studies in yeast and human cells that it acts downstream of the target-of-rapamycin (TOR) and the insulin-sensitive PI3 kinase pathways to control rapamycin-sensitive transcriptional programs. Thus, it appears that URI participates in signalling circuits dedicated, at least in part, to the integration of diverse metabolic and hormonal cues to control cell growth and division. Recently, we have begun to investigate the function of the URI-1 ortholog in C. elegans. We found that uri-1 encodes a germ line-enriched transcript whose protein product is critically important for germ cell proliferation. More specifically, we observed that URI-1-deficient cells block at prophase of the mitotic division cycle and display DNA breakage as evidenced by the appearance of HUS-1::GFP foci formation, implying that one or more functions of URI-1 might be linked, directly or indirectly, to the suppression of DNA damage and cell cycle arrest. Moreover, uri-1 mutants or cells depleted of URI-1 function display also increased germ line apoptosis in the meiotic compartment. Notably, the latter is a p53-dependent phenomenon, which in turn suggest that it is the result of genotoxic DNA damage. These results, taken together, imply key roles for C. elegans URI-1 in signaling circuits dedicated, in part, to genomic integrity control and the suppression of cell cycle arrest and apoptosis.

Diana David-Rus et al. (2004) East Coast Worm Meeting "Tracking the mid-life crisis of C. elegans"

Uri Einav, Patrick Nef, Eytan Domany, Peter J Schmeissner, Monica Driscoll, Diana David-Rus, Christophe Grundschober, Beate Hartmann, Garth Patterson

[East Coast Worm Meeting, 2004]

In an effort to better understand the biology of aging with an emphasis on mid-life changes that influence healthspan, we have undertaken a DNA microarray analysis of global gene expression profiles over time using Affymetrix gene chip arrays. Our experiment includes time points including the reproductive and post-reproductive periods, with a series of consecutive mid-life time points being covered. Studies in our lab and others have suggested that critical events during the mid-life of the nematode can influence the aging of this organism. For our analyses, we used supervised and unsupervised methods, including a clustering method developed in the Domany lab. Interestingly, we find a sharp change in the transcriptional levels of numerous genes at about 10 days post egg-lay. This abrupt change in gene expression on day 10 is consistent with a window of time identified previously by our lab as a time when mutations in the age-1 gene are able to delay the deterioration of muscle tissue (Herndon et al., 2002, Nature, 419: 808-14). The abrupt change also correlates with a transition point at which autofluorescent biomarkers accumulate (see abstract by Gerstbrein et al., this volume). Since two similar microarray experiments already have been performed (Lund et al., 2001, Curr Biol. 12(18): 1566-73; Murphy et al., 2003, Nature, 424(6946):277-83), we attempted a detailed cross-comparison between data from all three experiments, using non-parametric techniques. Again, a dramatic change in gene expression was observed for some genes at time points corresponding to our day 10 time point. Approximately 100 genes show significant changes in gene expression over adulthood in all three studies. These expression changes might be relevant to rapid end-stage deterioration in old nematodes.

Diana David-Rus et al. (2004) East Coast Worm Meeting "Tracking the mid-life crisis of C. elegans"

Christophe Grundschober, Garth Patterson, Uri Einav, Eytan Domany, Beate Hartmann, Patrick Nef, Peter J Schmeissner, Diana David-Rus, Monica Driscoll

[East Coast Worm Meeting, 2004]

In an effort to better understand the biology of aging with an emphasis on mid-life changes that influence healthspan, we have undertaken a DNA microarray analysis of global gene expression profiles over time using Affymetrix gene chip arrays. Our experiment includes time points including the reproductive and post-reproductive periods, with a series of consecutive mid-life time points being covered. Studies in our lab and others have suggested that critical events during the mid-life of the nematode can influence the aging of this organism. For our analyses, we used supervised and unsupervised methods, including a clustering method developed in the Domany lab. Interestingly, we find a sharp change in the transcriptional levels of numerous genes at about 10 days post egg-lay. This abrupt change in gene expression on day 10 is consistent with a window of time identified previously by our lab as a time when mutations in the age-1 gene are able to delay the deterioration of muscle tissue (Herndon et al., 2002). The abrupt change also correlates with a transition point at which autofluorescent biomarkers accumulate (see abstract by Gerstbrein et al., this volume). Since two similar microarray experiments already have been performed (Lund et al., 2001, Curr Biol. 12(18): 1566-73; Murphy et al., 2003, Nature, 424(6946):277-83), we attempted a detailed cross-comparison between data from all three experiments, using non-parametric techniques. We found approximately 100 genes showing changes in gene expression over adulthood common to all three studies. These expression changes might be relevant to rapid end-stage deterioration in old nematodes.

Diana David-Rus et al. (2005) International Worm Meeting "A search for mid-life gene expression changes that might influence healthspan"

Patrick Nef, Peter J Schmeissner, Beate Hartmann, Diana David-Rus, Monica Driscoll, Eytan Domany, Christophe Grundschober, Garth Patterson, Uri Einav

[International Worm Meeting, 2005]

Studies in our and other labs have suggested that critical events during the mid-life of the nematode can influence the aging and lifespan of this organism. In an effort to better understand the biology of aging with an emphasis on mid-life changes that influence healthspan, we performed a DNA microarray analysis of global gene expression profiles over time using Affymetrix gene chip arrays. Our experiment includes time points covering the reproductive and post-reproductive periods, with a series of consecutive mid-life time points. For our analyses, we used unsupervised methods, including a clustering method called Two-Way SPC (see. Domany et al.,Phys. Rev.Lett 76,3521). The method is actually a new approach to clustering, based on rules which can be described with help of statistical mechanics. Interestingly, we do find a sharp change in the transcriptional levels of numerous genes at about 10 days post egg-lay. This abrupt change in gene expression on day 10 of adulthood is consistent with a transition point at which potentially harmful autofluorescent biomarkers accumulate at accelerated rates (see abstract by Gerstbrein et al.) and at which age-related muscle decline may also accelerate. Since similar microarray experiments have been published (Lund et al., 2001, Curr Biol. 12(18): 1566-73; Murphy et al., 2003, Nature, 424(6946):277-83), we attempted a detailed cross-comparison between data from all three experiments, using again unsupervised, as well as supervised techniques. From the supervised technique we found approximately 100 genes that change expression during adult lifespan that are common to all three studies. We consider that these expression changes might be relevant to rapid end-stage deterioration in old nematodes.