DNA-binding proteins are unable to bind their cognate DNA recognition sequence because of steric hindrance from an attached methyl group.
A more predominant mechanism is mediated via a group of proteins with the capacity to read the epigenetic methyl-CpG code: the methyl-CpG-binding proteins.
Thus far, six methyl-binding proteins have been described. MBD1, MBD2, MBD3, MECP2, and KAISO are all involved in transcriptional repression, whereas MBD4 functions in DNA mismatch repair.
Methyl-CpG-binding proteins associate with histone modifying enzymes to maintain transcriptional silence, and methyl-DNA-binding proteins have been found associated with aberrantly methylated promoter regions of cancer-relevant genes such as p16 (CDKN2A) and MGMT.
Although MECP2, MBD2, and MBD4 have been found down-regulated in human cancers, perhaps surprisingly, no firm cancer connections have been established for any of the methyl-binding proteins.
MBD1 and MBD2 reside on human chromosome 18q21, a region frequently lost in cancer, but mutation analysis from human lung and colon cancers revealed few changes in MBD1 or MBD2, indicating a limited role for these proteins in cancer.
By extension, mouse knockout studies have not demonstrated important tumor-suppressor functions for MECP2, although long-term studies have been precluded, as these mice succumb early in life to neurological disorders (Chen et al. 2001; Guy et al. 2001).
In both mice and humans, mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome; however, patients with Rett syndrome do not appear to be predisposed to cancer development (Amir et al. 1999; Chen et al. 2001; Guy et al. 2001).
Also, Mbd2 deficiency does not predispose to tumor formation. On the contrary, when bred onto a bona fide model for intestinal cancer, the Apcmin mouse, loss of Mbd2 significantly delays tumorigenesis (Sansom et al. 2003).
Furthermore, MBD2 knockdown in human cancer cell lines was found to suppress tumorigenesis in a mouse xenograft model (Ivanov et al. 2003; Campbell et al. 2004).
Being the functional interpreters of DNA methylation, prominent roles for methyl-DNA-binding proteins in cancer could be envisioned.
The lack evidence supporting this could reflect the two-faced nature of DNA methylation: promoting oncogenesis via tumor-suppressor hypermethylation and protecting genome integrity through repression of repetitive DNA.
Also, additional methyl-binding proteins lacking the classical methyl-binding domain may yet be discovered.