Event Details:
This collaborative seminar is a joint effort of the Knight Initiative for Brain Resilience and the Paul F. Glenn Center for Biology of Aging Research.
To support our researchers' participation in this open science "lab-meeting style" exchange of ideas, these seminars are not streamed/recorded and are only open to members of the Stanford community.
Tanya T. Paull, Burl G. and Lorene L. Rogers Chair in Human Health, Professor of Oncology
DNA damage and cerebellar ataxia: roles for transcription stress, PARP, and R-loops in ATM-associated neurodegeneration
The Ataxia-Telangiectasia mutated (ATM) protein is a key regulator of checkpoint activation and homologous recombination in response to DNA double strand breaks (DSBs). In addition, ATM can be activated independently of MRN and DNA through direct oxidation, and ATM acts a redox sensor for oxidative stress in mammalian cells. In humans, loss of ATM leads to cancer predisposition as well as early childhood-onset neurodegeneration of the cerebellum. We have investigated the mechansims of ATM activation by DNA damage and reactive oxygen species in human cells and demonstrated roles for ATM in DNA damage responses as well as autophagy, regulation of reactive oxygen levels, and maintenance of protein homeostasis. Our recent studies have focused on investigation of human cerebellum and cortex tissues from A-T patients, which indicate a widespread aggregation of proteins and transcription alterations that are specific to the cerebellum tissue. In post-mitotic neurons in vitro, it is clear that these events are due to accumulation of transcription stress, single-strand breaks, and poly-ADP-ribose activity. Based on these observations we propose a model in which reactive oxygen species, in combination with active transcription, generates DNA damage that induces hyperPARylation and accumulation of aggregated proteins in the nucleus.C