PhD – The Flinders University of South Australia, Adelaide
- Molecular neurobiology
- Mouse models of human disease
- Brain tumors
- Tumor suppressors
Our goal is to understand the role of the DNA damage response in the nervous system, and how this functions to prevent disease. The response to genotoxic stress is a prerequisite for development of the nervous system. Mutations in a variety of DNA damage-response factors can lead to human diseases that are characterized by pronounced neuropathology. In many of these syndromes the neurological component is amongst the most deleterious aspects of the disease. Because the nervous system poses a particular challenge in terms of clinical intervention, understanding how DNA repair deficiency impacts the nervous system will be important for design of therapies targeted at ameliorating neuropathology including neurodegeneration and brain tumors.
General overview of current work in the lab:
- ATM signaling: ATM is a serine/threonine kinase important for neural homeostasis. This kinase is primarily important for responding to DNA breaks that occur during development of the nervous system. Defects in each can lead to human syndromes with pronounced neuropathology. We are working to understand the role of ATM in the nervous system and how it functions to prevent neurodevelopmental defects.
Read more about ATM signaling.
- DNA strand break repair: DNA damage can lead to a variety of DNA lesions including DNA double-strand or single-strand breaks, and a failure to respond to either type of strand breaks underpins a variety of human neurodegenerative syndromes. Our work aims to understand the specific spatiotemporal requirements for these repair pathways during development and maintenance of the nervous system, and how these repair pathways are coordinated to prevent various neurological diseases.
Read more about DNA strand break repair.
- DNA damage and brain tumors: There is an increasing link between defective responses to DNA damage and tumorigenesis. In many human DNA repair syndrome cancer is a common event. Our studies on DNA repair in the nervous system has also directly linked failed repair with brain tumors. Ongoing work in the lab aims at understanding how DNA repair defects contribute to different types of brain tumors, and how these brain tumor models can be used to develop therapeutic agents to treat brain malignancies.
Read more about DNA damage and brain tumors.
Katyal S, Lee Y, Nitiss KC, Downing SM, Zhao J, Shimada M, Russell HR, Petrini JH, Nitiss JL, McKinnon PJ. Aberrant Topoisomerase-1-DNA Lesions are Pathogenic in Neurodegenerative Genome Instability Syndromes. Nature Neuroscience 17(6):813-821, 2014.
McKinnon PJ. TDP2 Keeps the brain healthy. Nature Genetics 46(5);419-21, 2014.
McKinnon PJ. Maintaining genome stability in the nervous system. Nature Neuroscience 16(11):1523-1529, 2013.
Lee Y, Katyal S, Downing SM, Zhao J, Russell HR, McKinnon PJ. Neurogenesis requires TopBP1 to prevent catastrophic replication-associated DNA damage in early progenitors. Nature Neuroscience 15:819-826, 2012.
Lee Y, Shull ERP, Frappart P-O, Katyal S, Enriquez-Rios V, Zhao J, Russell HR, Brown EJ, McKinnon PJ. ATR maintains select progenitors during nervous system development. EMBO J 31:1177-89, 2012.
Gao Y, Katyal S, Lee Y, Zhao J, Rehg JE, Russell HR, McKinnon PJ. DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature 471(7337):240-4, 2011.
Simsek D, Furda A, Gao Y, Artus J, Brunet E, Hadjantonakis AK, Van Houten B, Shuman S,McKinnon PJ, Jasin M. Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair. Nature 471(7337):245-8, 2011.
Murga M, Bunting S, Montana MF, Soria R, Mulero F, Canamero M, Lee Y, McKinnon PJ, Nussenzweig A, Fernandez-Capetillo O. A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nature Genetics 41(8):891-8, 2009.
Lee Y, Katyal S, Li Y, El-Khamisy SF, Russell HR, Caldecott KW, McKinnon PJ. The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1. Nature Neuroscience 12:973-980, 2009.
Shull ER, Lee Y, Nakane H, Stracker TH, Zhao J, Russell HR, Petrini JH, McKinnon PJ. Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes & Development 23:171-180, 2009.
McKinnon PJ. DNA repair deficiency and neurological disease. Nature Reviews Neuroscience 10:100-112, 2009.
Frappart PO, Lee Y, Russell HR, Chalhoub N, Wang YD, Orii KE, Zhao J, Kondo N, Baker SJ,McKinnon PJ. Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. PNAS (USA) 106:1880-1885, 2009.
Katyal S, el-Khamisy SF, Russell HR, Li Y, Ju L, Caldecott KW, McKinnon PJ. TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. The EMBO J 26:4720-4731, 2007.
Frappart PO, Lee Y, Lamont J, McKinnon PJ. BRCA2 is required for neurogenesis and suppression of medulloblastoma. The EMBO journal 26:2732-2742, 2007.
Ahel I, Rass U, El-Khamisy SF, Katyal S, Clements PM, McKinnon PJ, Caldecott KW, West SC. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature 443:713-716, 2006.
Orii KE, Lee Y, Kondo N, McKinnon PJ. Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. PNAS (USA) 103:10017-10022, 2006.
Baker SJ, McKinnon PJ. Tumour-suppressor function in the nervous system. Nature Reviews Cancer 4:184-196, 2004.
Last update: February 2015