DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms

University Of Minnesota, Minneapolis MN

Investigators

Linked publications, trials & patents

Abstract

DNA-protein cross-links (DPCs) are formed when proteins become covalently bound to DNA form spontaneously as a result of normal cellular processes such as lipid peroxidation, histone demethylation, DNA replication, transcription, and DNA repair. DPCs can be induced by exposure to anti-tumor drugs, transition metals, UV light, and γ-radiation. DPCs interfere with many biological processes and are implicated in the accelerated aging and increased cancer incidence observed in Ruijs-Aalfs syndrome patients. The goal of our currently funded application is to map DPC lesions along the genome, investigate how human cells recognize and remove these exceedingly bulky DPC lesions, and to identify the mechanisms by which they cause mutagenicity and cell death. The present supplement application with address the potential involvement of DPCs in Alzheimer’s disease and other dementias. Our central hypothesis is that that DNA-protein cross-linking induced by endogenous aldehydes and environmental metals contribute to the etiology of AD and other age-related neurodegenerative diseases. Our research plan focuses on two Aims. First, will characterize DNA-protein cross- linking in brains of healthy individuals of increasing age, patients with mild cognitive decline, Alzheimers’s disease patients, and nondemented elderly controls using novel mass spectrometry based experimental methodologies already developed in our laboratory. These studies will identify the proteins participating in DPC formation in human brain and test a possible association of DNA-protein cross-linking with aging and neurodegenerative disease. Second, we will identify the mechanisms of DPC formation in human brain but correlating DPC levels in human brain to the concentrations of heavy metals, endogenous aldehydes, and reactive oxygen species. These experiments will help identify the sources of DNA-protein cross- links in human brain. Collectively, our proposed studies will facilitative future prevention and treatment efforts by providing additional insight into the etiology of AD.