BECN1/Atg6 is an important component of the autophagy pathway in mammals and yeast, and in C. elegans plays a crucial role in the process of organismal aging. Mammalian BECN1 protein has also been shown to act as a tumor suppressor protein, and to promote genomic stability. However, the mechanism by which BECN1 functions to promote genomic stability is not well understood. Autophagy is a key process by which cellular components are degraded and recycled and this process plays important roles during organismal development and aging. For instance, we, and others have shown that autophagy is upregulated in several C. elegans mutants with extended longevity, including insulin/IGF-1 receptor daf-2 mutants. Intriguingly, such mutants require autophagy genes, e.g. bec-1/becn1, to live long. We have recently discovered a role for BEC-1/BECN1 and several other autophagy genes in promoting cell cycle progression and establishing a germline stem cell population in L4 animals. This process requires autophagy gene activity non-cell-autonomously, and can be rescued by expression of BEC-1 in muscle and hypodermis. We have also reported a role for BEC-1 and CEP-1/p53 in DNA damage repair (Hoffman, et al., 2014) and we have preliminary data that indicates a role for BEC-1/BECN1 in promoting meiotic fidelity. Similarly, a recent report also indicates a role for CEP-1/p53 in meiosis (Mateo et al., 2016). We hypothesize that other autophagy genes will be involved and plan to investigate the mechanism by which BEC-1/BECN1 and autophagy genes are required for DNA damage repair and meiosis. To this end, we propose to address three specific aims: First, we will further our knowledge as to the mechanisms by which autophagy genes are required for stem cell proliferation; (2) the mechanism for how autophagy genes are required for meiosis, and (3) whether BEC-1 is required for DNA damage repair, for the choice of repair pathway, between the homologous recombination and nonhomologous end joining pathways. The spatial and temporal requirements for BEC-1, ATG-18, ATG-7 and CEP-1 will be elucidated in their role in meiosis and the DNA damage response.
(3 lines, lay person): This study aims to explore the role of BEC-1 ?mediated autophagy ? a cellular pathway by which cytoplasmic components are recycled ? in stem cell proliferation, meiosis and the DNA damage response by examining the role of the autophagy genes in mitosis, meiosis, and the maintenance of genome integrity.
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