Genotoxic stress, DNA repair and metabolism
DNA lesions are dealt with through a network of signaling and repair pathways that recognize and eliminate the damage. In addition to impacting DNA repair processes, genotoxic stress broadly impacts a wide range of cellular processes, halting cell division and activating apoptosis or cellular senescence, depending on the context of genotoxin and cell type. DNA damage can also directly or indirectly impinge on cellular energy metabolism. In fact, many human syndromes and mouse models of defective DNA damage repair display alterations in growth, energy metabolism and mitochondrial function. However, the nature of these changes in energy metabolism and their relation to genotoxic stress remain unclear.
Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure, lipodystrophy, vision and hearing loss, neurodegeneration, and photosensitivity without prevalence of skin cancer. Most CS cases are caused by alterations in one of two proteins, CSA or CSB. These proteins share a common function in transcription-coupled nucleotide excision DNA repair (TC-NER) in the nucleus via removal of lesions from DNA, often caused by ultraviolet light, that hinder RNA polymerases and block transcription.
We work on a mouse model of CS that recapitulates severe and progressive symptoms seen in CS patients including lipodystrophy and neurological dysfunction (Brace 2013). Ongoing studies in the lab are focused on elucidating the effects of genotoxic stress on metabolism in vivo and in cells in vitro in mouse models of CS as well as in normal aging.
Susa D, Mitchell JR, Verweij M, van de Ven M, Roest H, van den Engel S, Bajema I, Mangundap K, Ijzermans JN, Hoeijmakers JH, de Bruin RW. Congenital DNA repair deficiency results in protection against renal ischemia reperfusion injury in mice. Aging Cell, 2009. Volume(2): p. 192-200. PMID: 19338497
Vose S, Mitchell JR. Relationship Between DNA Damage and Energy Metabolism: Evidence from DNA Repair Deficiency Syndromes. DNA Repair and Human Health. ed. Vengrova S. Oct 2011. ISBN 978-953-307-612-6
van de Ven M, Andressoo JO, van der Horst GTJ, Hoeijmakers JHJ, Mitchell JR. Effects of compound heterozygosity at the Xpd locus on cancer and ageing in mouse models. DNA Repair 2012 Nov 1:11(11):874-83. PMID: 23046824
Brace L, Vose SC, Vargas DF, Zhao S, Wang X-P, Mitchell JR. Lifespan extension by dietary intervention in a mouse model of Cockayne Syndrome uncouples early postnatal development from segmental progeria. Aging Cell 2013 Dec;12(6):1144-7. PMID: 23895664
Fang EF, Scheibye-Knudsen M, Brace L, Mitchell JR, Nilsen H, Croteau DL, Bohr VA. Defective mitophagy in xeroderma pigmentosum group A via attenuation of the NAD+/SIRT1 pathway. Cell 2014 May 8;157(4):882-96. PMID: 24813611.