dxy

Maintainance  of  DNA  Methylation.  (A-B)The  preferential  substrate  for  the maintenance cytosine methyltransferase, DNMT1, is hemi-methylated CpG sites resulting from newly synthesized DNA in somatic cells. DNMT1 is present at the replication fork, and  functions  with  the  help  of  partner  proteins  including  UHRF  and  PCNA  .  (C)  Post-replication, DNMT1 and a methyl-CpG binding protein MBD4 can be localized together at DNA damage sites and may be part of cellular pathway response that activates apoptosis. MBD4 interacts directly with both DNMT1 and MLH1 leading to recruitment of all three at  DNA  damage  sites.  (D)  MBD4  has  also  been  shown  to recruit  Fas-associated  death domain protein (FADD), which bridges death receptors with initiator caspases. FADD may also  be  an  apoptotic  effector  via  MBD4.  (E)  Several  active  DNA  demethylation  models have  been  proposed.  MBD4  was  reported  to  execute  active DNA  demethylation  at  the CYP27B1 promoter in response to PTH (Parathyroid Hormone) signaling. Similarly TDG (Thymine DNA glycosylase) can also interact with Dnmt3A and Dnmt3B and function as 5meC  glycosylase  activity  against  hemi-methylated  DNA  with  the  same  weak  excision activity as MBD4. In zebrafish embryos Aid, Mbd4 and the DNA repair protein Gadd45a may  cooperate  to  induce  demethylation.  Thymine  glycosylases  such  as  TDG  and  MBD4 may function on deamination of 5-methyl-cytosine by repairing the resulting mismatch. (F) TET1 is capable of acting on both fully methylated and hemi-methylated DNA, producing 5-hydroxymethylcytosine  (5hmC)  in  DNA,  which  may  also  act  in  signaling  pathways associated with turnover and maintenance of the epigenome.