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.