Developmental arrest of Caenorhabditis elegans BRAP-2 mutant exposed to oxidative stress is dependent on BRC-1.
Oxidative damage by reactive oxygen species is believed to be a contributor to the development of cancer and the physiological deterioration associated with aging. In this report, we describe the effect of reactive oxygen species exposure to a developing Caenorhabditis elegans organism containing a deletion in the homolog of BRCA1-associated protein 2 (BRAP-2). A mutant containing a deletion of brap-2 was highly sensitive to oxidizing conditions and demonstrated early larval arrest and lethality at low concentrations of the oxidative stress-inducing drug paraquat compared with the wild-type. This developmental arrest occurred early in the L1 stage and was dependent specifically on the function of the C. elegans ortholog of BRCA-1 tumor suppressor brc-1. We also show that developmental arrest in brap-2 mutants when exposed to oxidative stress was due to enhanced expression levels of the cell cycle inhibitor cki-1, and this increase in the expression levels of cki-1 requires brc-1 in brap-2 mutant animals. Our findings demonstrate that BRAP-2 is necessary for preventing an inappropriate response to elevated levels of reactive oxygen species by countering premature activation of BRC-1 and CKI-1.
Koon
Janet C
JC
Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
Kubiseski
Terrance J
TJ
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006540:Herbicides / Q000494:pharmacology; D007814:Larva / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010269:Paraquat / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
C528463:BRC-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D006540:Herbicides; D017382:Reactive Oxygen Species; C115024:cki-1 protein, C elegans; D010269:Paraquat