5-halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl-CpG-binding domain of methyl-CpG-binding protein 2 (MeCP2).
Perturbations in cytosine methylation signals are observed in the majority of human tumors; however, it is as yet unknown how methylation patterns become altered. Epigenetic changes can result in the activation of transforming genes as well as in the silencing of tumor suppressor genes. We report that methyl-CpG-binding proteins (MBPs), specific for methyl-CpG dinucleotides, bind with high affinity to halogenated pyrimidine lesions, previously shown to result from peroxidase-mediated inflammatory processes. Emerging data suggest that the initial binding of MBPs to methyl-CpG sequences may be a seeding event that recruits chromatin-modifying enzymes and DNA methyltransferase, initiating a cascade of events that result in gene silencing. MBD4, a protein with both methyl-binding and glycosylase activity demonstrated repair activity against a series of 5-substituted pyrimidines, with the greatest efficiency against 5-chlorouracil, but undetectable activity against 5-chlorocytosine. The data presented here suggest that halogenated pyrimidine damage products can potentially accumulate and mimic endogenous methylation signals.
Valinluck
Victoria
V
Department of Biochemistry and Microbiology, School of Medicine, Loma Linda University Loma Linda, CA 92350, USA.
Liu
Pingfang
P
Kang
Joseph I
JI
Burdzy
Artur
A
Sowers
Lawrence C
LC
D044503:5-Methylcytosine / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry* / Q000378:metabolism*; D018899:CpG Islands; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004706:Endodeoxyribonucleases / Q000378:metabolism; D006219:Halogens / Q000737:chemistry; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry*; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006219:Halogens; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D011743:Pyrimidines; D012097:Repressor Proteins; D044503:5-Methylcytosine; D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human; D045647:DNA Glycosylases