PMID- 10499592
OWN - NLM
STAT- MEDLINE
DCOM- 19991014
LR  - 20131121
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 401
IP  - 6750
DP  - 1999 Sep 16
TI  - The thymine glycosylase MBD4 can bind to the product of deamination at methylated
      CpG sites.
PG  - 301-4
AB  - In addition to its well-documented effects on gene silencing, cytosine
      methylation is a prominent cause of mutations. In humans, the mutation rate from 
      5-methylcytosine (m5C) to thymine (T) is 10-50-fold higher than other transitions
      and the methylated sequence CpG is consequently under-represented. Over one-third
      of germline point mutations associated with human genetic disease and many
      somatic mutations leading to cancer involve loss of CpG. The primary cause of
      mutability appears to be hydrolytic deamination. Cytosine deamination produces
      mismatched uracil (U), which can be removed by uracil glycosylase, whereas m5C
      deamination generates a G x T mispair that cannot be processed by this enzyme.
      Correction of m5CpG x TpG mismatches may instead be initiated by the thymine DNA 
      glycosylase, TDG. Here we show that MBD4, an unrelated mammalian protein that
      contains a methyl-CpG binding domain, can also efficiently remove thymine or
      uracil from a mismatches CpG site in vitro. Furthermore, the methyl-CpG binding
      domain of MBD4 binds preferentially to m5CpG x TpG mismatches-the primary product
      of deamination at methyl-CpG. The combined specificities of binding and catalysis
      indicate that this enzyme may function to minimize mutation at methyl-CpG.
FAU - Hendrich, B
AU  - Hendrich B
AD  - Institute of Cell and Molecular Biology, University of Edinburgh, UK.
FAU - Hardeland, U
AU  - Hardeland U
FAU - Ng, H H
AU  - Ng HH
FAU - Jiricny, J
AU  - Jiricny J
FAU - Bird, A
AU  - Bird A
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Dinucleoside Phosphates)
RN  - 0 (Nucleic Acid Heteroduplexes)
RN  - 2382-65-2 (cytidylyl-3'-5'-guanosine)
RN  - 56HH86ZVCT (Uracil)
RN  - 9007-49-2 (DNA)
RN  - EC 3.1.- (Endodeoxyribonucleases)
RN  - EC 3.1.- (MBD4 protein, human)
RN  - EC 3.1.25.1 (Deoxyribonuclease (Pyrimidine Dimer))
RN  - EC 3.2.2.- (Mbd4 protein, mouse)
RN  - QR26YLT7LT (Thymine)
SB  - IM
EIN - Nature 2000 Mar 30;404(6777):525
MH  - Amino Acid Sequence
MH  - Animals
MH  - DNA/*metabolism
MH  - DNA Methylation
MH  - *DNA Repair
MH  - Deoxyribonuclease (Pyrimidine Dimer)
MH  - Dinucleoside Phosphates/*metabolism
MH  - Endodeoxyribonucleases/*metabolism
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Nucleic Acid Heteroduplexes
MH  - Sequence Homology, Amino Acid
MH  - Substrate Specificity
MH  - Thymine/metabolism
MH  - Uracil/metabolism
EDAT- 1999/09/28 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/09/28 09:00
PHST- 1999/09/28 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/09/28 09:00 [entrez]
AID - 10.1038/45843 [doi]
PST - ppublish
SO  - Nature. 1999 Sep 16;401(6750):301-4. doi: 10.1038/45843.