DNA mismatch repair and DNA methylation in adult brain neurons

DNA repair is essential for maintaining the integrity of the nucleotide sequence of cellular DNA over time. Although much information has accumulated recently on the mechanisms of DNA repair in cultured cells, little is known about the DNA repair capabilities of cells in the adult brain. In the present study, we have investigated the capacity of nuclear extracts from adult rodent brain neurons to carry out DNA mismatch repair. We focused on the repair of G.T and G.U mismatches, which are caused by deamination of 5-methyl cytosine to thymine, or cytosine to uracil, respectively, because these are the only types of mismatches that can arise in nondividing cells. We found that nuclear extracts from adult brain neurons can correct G.T and G.U mismatches, restoring them to G:C base pairs. Several other types of DNA mismatches could not be processed. These data provide the first direct demonstration that neurons in the adult mammalian brain have the capability to carry out DNA mismatch repair. We also we report that adult brain contains high levels of DNA methyltransferase (MTase) activity. We propose that one function of DNA MTase in the adult brain is to remethylate newly incorporated cytosine residues from G.T mismatch repair after deamination of 5-methyl cytosine, thereby maintaining the original pattern of DNA methylation. The high levels of brain DNA MTase suggest further that this enzyme has additional functions in the brain.

[1]  A. Alcivar-Warren,et al.  Developmental and hormonal regulation of DNA methyltransferase in the rat testis. , 1995, Biology of reproduction.

[2]  A. Sancar.  Mechanisms of DNA excision repair. , 1994, Science.

[3]  P. Modrich,et al.  Mismatch repair, genetic stability, and cancer. , 1994, Science.

[4]  P. Hanawalt.  Transcription-coupled repair and human disease. , 1994, Science.

[5]  J. Burbach,et al.  Frameshift mutations at two hotspots in vasopressin transcripts in post-mitotic neurons. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[6]  P. Jones,et al.  The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. , 1994, Nucleic acids research.

[7]  T. Ono,et al.  Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. , 1994, Differentiation; research in biological diversity.

[8]  J. Cleaver.  It was a very good year for DNA repair , 1994, Cell.

[9]  P. Karmakar.  Studies on DNA damage and repair in human cells , 1994 .

[10]  P. Karran,et al.  Incision at DNA G.T mispairs by extracts of mammalian cells occurs preferentially at cytosine methylation sites and is not targeted by a separate G.T binding reaction. , 1993, Biochemistry.

[11]  J. Jiricny,et al.  The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells. , 1993, The Journal of biological chemistry.

[12]  A. Coxon,et al.  Cytosine methylation The pros and cons of DNA methylation , 1993, Current Biology.

[13]  T. Lindahl.  Instability and decay of the primary structure of DNA , 1993, Nature.

[14]  R. Day,et al.  DNA-substrate sequence specificity of human G:T mismatch repair activity. , 1993, Nucleic acids research.

[15]  J. Hoeijmakers,et al.  Structure and expression of the excision repair gene ERCC6, involved in the human disorder Cockayne's syndrome group B. , 1993, Nucleic acids research.

[16]  Y. Weng,et al.  Developmental regulation of the base excision repair enzyme uracil DNA glycosylase in the rat. , 1993, Mutation research.

[17]  P. Mazzarello,et al.  DNA repair mechanisms in neurological diseases: facts and hypotheses , 1992, Journal of the Neurological Sciences.

[18]  Adrian Bird,et al.  The essentials of DNA methylation , 1992, Cell.

[19]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[20]  B. Trask,et al.  Isolation and characterization of the cDNA encoding human DNA methyltransferase. , 1992, Nucleic acids research.

[21]  G. Dianov,et al.  Generation of single-nucleotide repair patches following excision of uracil residues from DNA , 1992, Molecular and cellular biology.

[22]  J. Mašín,et al.  Two nicking enzyme systems specific for mismatch-containing DNA in nuclear extracts from human cells. , 1991, The Journal of biological chemistry.

[23]  J. Jiricny,et al.  Mismatch-specific thymine DNA glycosylase and DNA polymerase beta mediate the correction of G.T mispairs in nuclear extracts from human cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Jiricny,et al.  In vitro correction of G o T mispairs to G o C pairs in nuclear extracts from human cells , 1989, Nature.

[25]  H. Bachelard,et al.  Studies on DNA Damage and Repair in the Mammalian Brain , 1988, Journal of neurochemistry.

[26]  J. Jiricny,et al.  A specific mismatch repair event protects mammalian cells from loss of 5-methylcytosine , 1987, Cell.

[27]  W. Bradley,et al.  Deficient DNA repair in amyotrophic lateral sclerosis cells , 1987, Journal of the Neurological Sciences.

[28]  C. Kuenzle.  Enzymology of DNA replication and repair in the brain , 1985, Brain Research Reviews.

[29]  R. Tarone,et al.  Parkinson's disease and Alzheimer's disease: hypersensitivity to X rays in cultured cell lines. , 1985, Journal of neurology, neurosurgery, and psychiatry.

[30]  D. Scudiero,et al.  Hypersensitivity to N-methyl-N'-nitro-N-nitrosoguanidine in fibroblasts from patients with Huntington disease, familial dysautonomia, and other primary neuronal degenerations. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[31]  U. Hübscher,et al.  DNA polymerase beta from brain neurons is a repair enzyme. , 1979, European journal of biochemistry.

[32]  R. W. Turkington,et al.  Methylation of deoxyribonucleic acid during hormonal stimulation of mammary cells in vitro. , 1971, The Journal of biological chemistry.

[33]  R. Burdon,et al.  The in vivo methylation of DNA in mouse fibroblasts. , 1969, Biochimica et biophysica acta.

[34]  J. Cleaver.  Defective Repair Replication of DNA in Xeroderma Pigmentosum , 1968, Nature.