Identifying the role of DAP-1 and H3.3 histones in starvation and longevity in Caenorhabditis elegans

  • Yasir Malik

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Abstract

    All animals have to adapt to fluctuation in the availability of food. Thus, mechanisms have evolved to help organisms adapt to the intermittent availability of food; especially during periods of starvation viability has to be maintained. At the same time, a growing body of evidence suggests that transient or intermittent starvation is beneficial for healthy ageing, and indeed leads to increased lifespan. This has been demonstrated in model organisms including Caenorhabditis elegans. Recently, multiple starvation studies in C. elegans have unveiled novel mechanisms which regulate important cellular phenomena like fatty-acid metabolism, redox regulation and macroautophagy. Nevertheless, many of the regulatory circuits needed for starvation survival remain to uncovered. In addition, the emerging linkage between mild starvation and increased longevity is a topic area of research.

    My PhD thesis is based on a previous proteomics study conducted by the Gartner and Lamond labs, which investigated the global changes in protein expression upon starvation. The study analysed the change in proteome of C. elegans when worms were starved for 2-16 hours - a time period of starvation which can increase the mean lifespan of worms by up to 20%.

    The aim of my thesis was to follow up on some of the proteins found upregulated upon starvation and to investigate if they have a role in mediating survival to starvation and/or link between starvation and longevity. My thesis is focused on two proteins: HIS-71- a highly conserved histone H3 variant, and DAP-1- which is highly conserved in animals, but nevertheless poorly characterized. We found that HIS-71 is required for mediating increased longevity after intermittent starvation. We started to investigate the role of his-71 using double mutant analyses with TOR and Insulin signalling pathways, both known to affect ageing and starvation response.

    The main focus of my thesis turned out to be on DAP-1.

    The human DAP1 protein has been implicated in inhibiting autophagy during amino acid starvation in HeLa cells. We found that the C. elegans homolog DAP-1 is a general stress responsive protein whose impairment leads to decreased resistance towards many stresses including starvation. We provide evidence that DAP-1 inhibits autophagy during starvation and that it is required for an increase in lifespan upon restriction mediated increase in lifespan. We establish that the transcription factor DAF-16/FOXO which acts downstream of the Insulin-like/DAF-2 signalling pathway, also governs the expression of DAP-1 during starvation and thus facilitates organismal survival in response to starvation. Overall, we establish DAP-1 as important factor in regulating acute starvation, which impacts important cellular phenomena during starvation.
    Date of Award2019
    Original languageEnglish
    SupervisorAnton Gartner (Supervisor) & Angus Lamond (Supervisor)

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