page_title: Base excision repair
section_title: MBD4
hierarchical_section_title: Base excision repair / Epigenetic deficiencies in cancers / MBD4
caption_attribution_description: Deutsch: Desaminierung Cytosin zu UracilEnglish: Deamidation of cytosine to uracil
context_page_description: Base excision repair is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.
context_section_description: MBD4 (methyl-CpG-binding domain protein 4) is a glycosylase employed in an initial step of base excision repair.  MBD4 protein binds preferentially to fully methylated CpG sites and to the altered DNA bases at those sites.  These altered bases arise from the frequent hydrolysis of cytosine to uracil (see image) and hydrolysis of 5-methylcytosine to thymine, producing G:U and G:T base pairs.  If the improper uracils or thymines in these base pairs are not removed before DNA replication, they will cause transition mutations.  MBD4  specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites.  This is an important repair function since about 1/3 of all intragenic single base pair mutations in human cancers occur in CpG dinucleotides and are the result of G:C to A:T transitions.  These transitions comprise the most frequent mutations in human cancer.  For example, nearly 50% of somatic mutations of the tumor suppressor gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites.  Thus, a decrease in expression of MBD4 could cause an increase in carcinogenic mutations.
  MBD4 expression is reduced in almost all colorectal neoplasms due to methylation of the promoter region of MBD4.  Also MBD4 is deficient due to mutation in about 4% of colorectal cancers.
  A majority of histologically normal fields surrounding neoplastic growths (adenomas and colon cancers) in the colon also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue from individuals who never had a colonic neoplasm. This finding suggests that epigenetic silencing of MBD4 is an early step in colorectal carcinogenesis.
  In a Chinese population that was evaluated, the MBD4 Glu346Lys polymorphism was associated with about a 50% reduced risk of cervical cancer, suggesting that alterations in MBD4 may be important in cancer.
caption: Hydrolysis of cytosine to uracil
exif: {}