Andrea Brown

The Seven Deadly Pathways: A Boolean Model of Yeast Apoptosis in Response to Reactive Oxygen Species, DNA damage, and Salt

Class of 2022

Biography

  • Education
    • Concord-Carlisle High School, Concord, MA, 2018
    • The College of Wooster, BA in Biochemistry and Molecular Biology, 2022
    • Professional experience
    • The College of Wooster Biology Department, Research Assistant, Teaching Assistant, Building Monitor

IS Thesis Abstract

Apoptosis is a conserved stress-response process that ensures the destruction of damaged or old cells in a tissue or cell colony. Even single celled organisms such as yeast have programmed cell death pathways. Though these pathways have been evolving since their emergence, multiple characteristics of the process itself remain conserved. Stressors such as reactive oxygen species (ROS), DNA damage, starvation, and salt are shared activators of apoptosis in both mammalian cells and yeast. Moreover, apoptosis involves similar phenotypic changes such as blebbing, mitochondrial fission and failure, as well as DNA fragmentation. Despite these conserved processes, very few proteins involved in yeast apoptosis have homologues in mammals and vice versa. To better compare the two regulatory networks, we designed a detailed dynamic Boolean model of the interaction network that controls yeast apoptosis in response to three stressors: ROS, DNA damage, and salt. The core event all signals converge on is the destruction of the mitochondrial membrane integrity. ROS, for example, activates multiple pathways that simultaneously cause mitochondrial fission and membrane stress, until the outer mitochondrial membrane permeabilization (MOMP) is locked in by the activation of AAC. The resulting cytochrome c release is one of the few conserved molecular events leading to apoptosis. When apoptosis is caused by DNA damage, AAC is activated directly, leading to high ROS production / accumulation, which then triggers the remaining pathways such as mitochondrial fragmentation. contrast, an increase in NaCl levels directly activates the yeast metacaspase Yca1p. This upregulates ROS production and triggers mitochondrial stress, leading once more to MOMP and persistent high ROS. In addition to mimicking signal-induced apoptosis cascades observed in vivo, mutant versions of our model also reproduce experimental observations. Our model offers an intriguing case study for the evolutionarily conservation of processes involving mitochondrial dynamics and apoptosis, despite a near-complete replacement of the entire cast of its molecular regulatory network.

Figure 1. The Seven Deadly Pathways: mitochondrial failure is caused by several positive feedback loops that lock in yeast apoptosis. 
Figure 2. Andrea presenting her work at the Winter Q-Bio Conference, February, 2022

Webpage: https://www.linkedin.com/in/andrea-brown-6397ba194/