The Role of BRAP-2 in Caenorhabditis Elegans DNA Damage Induced Germline Apoptosis Development and Germline Health
D'Amora, Dayana Rita
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The DNA damage response protects the genome by executing processes that prevent the disruption of normal cell physiology and the inheritance of mutations. BRCA1 is an essential tumor suppressor gene that facilitates DNA repair, transcription and plays a more complex role in apoptosis. A novel BRCA1 binding protein known as BRAP2/IMP has been characterized as a RAS effector with ubiquitin ligase activity and as a cytoplasmic retention protein. BRAP2 is conserved in C. elegans, and is known as BRAP-2. Previously, we have shown that BRAP-2 is a negative regulator of SKN-1/Nrf2 dependent detoxification gene expression. In addition, brap-2 deletion mutants experience BRC-1 (BRCA1 ortholog) dependent larval arrest when exposed to oxidative stress. BRC-1 function in DNA repair is conserved in the germline, where a loss of brc-1 increases apoptosis. Due to the conservation of BRC-1 function in C. elegans and the genetic link between BRC-1 and BRAP-2 upon oxidative stress, in this study we examined the role of BRAP-2 in DNA damage induced germline apoptosis, C. elegans development and germline health. We found that brap-2 mutants display a reduction in DNA damage induced germline apoptosis and that apoptosis induced by loss of BRC-1 requires BRAP-2. We also found that a loss of PMK-1, SKN-1 and AKT-1 in brap-2 mutants increases apoptosis, indicating that a loss of BRAP-2 limits DNA damage induced germline apoptosis and promotes cell survival through regulation of the PMK-1 activated SKN-1 oxidative stress response pathway and Insulin/Insulin-like growth factor signaling. In addition, brap-2 mutants display defects in development, survival, brood size and germline morphology. Taken together, this suggests that BRAP-2 is required to promote DNA damage induced germline apoptosis by regulating pro-cell survival pathways and that BRAP-2 is required for proper C. elegans growth, development and germline health.