DNA Methyltransferase and DNA Repair Activity in the Rodent Brain

Brooks, P.

Abstract

DNA methylation is critically involved in the control of chromatin structure and gene expression. There are data in the literature suggesting that alcohol may influence DNA methylation patterns. Therefore, we are carrying out studies on the localization and expression of DNA methyltransferase (MTase), the enzyme responsible for DNA methylation, focusing on brain tissues. MTase mRNA and enzyme levels are being studied in different adult brain regions, as well as during development. The regulation of MTase in the adult brain by ethanol and acetaldehyde, by steroids, and other factors are being determined. As a sensitive measure of possible effects on methylation at a specific genomic loci, we will examine effects of ethanol on the expression of imprinted genes where transcriptional silencing is known to be mediated by DNA methylation. The expression of DNA methyltransferase in the adult brain led to the hypothesis that this enzyme may play a role in DNA repair. Therefore, we have initiated a series of studies on the capability of DNA repair processes by adult neurons. We have found that adult brain neurons can carry out select types of DNA mismatch repair, including G:T mismatch repair. In addition, we have shown that the adult brain contains enzymes that address oxidatively damaged DNA as well. Formerly titled: """"""""Expression and Regulation of DNA Methyltransferase in the Mammalian Brain""""""""

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AA000083-02
• Application #: 5200236
• Support Year: 2
• Fiscal Year: 1995

Institution

• Name: National Institute on Alcohol Abuse and Alcoholism
• Country: United States

Publications

Brooks, P J (2008) The 8,5'-cyclopurine-2'-deoxynucleosides: candidate neurodegenerative DNA lesions in xeroderma pigmentosum, and unique probes of transcription and nucleotide excision repair. DNA Repair (Amst) 7:1168-79

Nakane, Hironobu; Hirota, Seiichi; Brooks, Philip J et al. (2008) Impaired spermatogenesis and elevated spontaneous tumorigenesis in xeroderma pigmentosum group A gene (Xpa)-deficient mice. DNA Repair (Amst) 7:1938-50

Brooks, P J; Cheng, Tsu-Fan; Cooper, Lori (2008) Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage? DNA Repair (Amst) 7:834-48

Gorodetsky, Elena; Calkins, Sarah; Ahn, Julia et al. (2007) ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain. DNA Repair (Amst) 6:1698-707

Theruvathu, Jacob A; Jaruga, Pawel; Dizdaroglu, Miral et al. (2007) The oxidatively induced DNA lesions 8,5'-cyclo-2'-deoxyadenosine and 8-hydroxy-2'-deoxyadenosine are strongly resistant to acid-induced hydrolysis of the glycosidic bond. Mech Ageing Dev 128:494-502

Brooks, P J (2007) The case for 8,5'-cyclopurine-2'-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum. Neuroscience 145:1407-17

Marietta, Cheryl; Brooks, Philip J (2007) Transcriptional bypass of bulky DNA lesions causes new mutant RNA transcripts in human cells. EMBO Rep 8:388-93

Theruvathu, Jacob A; Jaruga, Pawel; Nath, Raghu G et al. (2005) Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde. Nucleic Acids Res 33:3513-20

Brooks, Philip J; Theruvathu, Jacob A (2005) DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. Alcohol 35:187-93

Jaruga, Pawel; Theruvathu, Jacob; Dizdaroglu, Miral et al. (2004) Complete release of (5'S)-8,5'-cyclo-2'-deoxyadenosine from dinucleotides, oligodeoxynucleotides and DNA, and direct comparison of its levels in cellular DNA with other oxidatively induced DNA lesions. Nucleic Acids Res 32:e87