期刊
NUCLEIC ACIDS RESEARCH
卷 33, 期 9, 页码 3057-3064出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gki612
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资金
- NATIONAL CANCER INSTITUTE [R01CA084487] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM050351] Funding Source: NIH RePORTER
- NCI NIH HHS [CA084487, R01 CA084487] Funding Source: Medline
- NIGMS NIH HHS [R01 GM050351, GM50351] Funding Source: Medline
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.
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