DNA (cytosine-5)-methyltransferase 3-like (DNMT3L) is an enzymatically inactive regulatory factor of de novoDNA methyltransferases DNMT3A and DNMT3AB [, , ]. It is related in sequence to DNMT3A and DNMT3B, but lacks cytosine methyltransferase activity due to the absence of catalytic residues. It recognises histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2 []. It interacts with transcription factors to target DNMT3L/DNMT3B to specific DNA sequences []. In mouse embryonic stem cells, DNMT3L functions as a negative regulator of methylation at promoters of bivalent genes whereas favours DNA methylation at gene bodies of housekeeping genes [].
This is a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, AD-DATRX) found in ATRX proteins. Chromatin-associated human protein ATRX was originally identified because mutations in the ATRX gene cause a severe form of syndromal X-linked mental retardation called ATR-X syndrome. Mutations or knockdown of ATRX expression cause diverse effects, including altered patterns of DNA methylation, a telomere-dysfunction phenotype, aberrant chromosome segregation, premature sister chromatid separation and changes in gene expression. ATRX localizes predominantly to large, tandemly repeated regions (such as telomeres, centromeres and ribosomal DNA) associated with heterochromatin, and studies show that it directs H3.3 deposition to pericentric and telomeric heterochromatin. The ADD domain of ATRX, in which most syndrome-causing mutations occur, engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. Mutations in the ATRX ADD domain cause mislocalization of ATRX protein to heterochromatin, and this may contribute to understanding the underlying etiology of ATRX syndrome. Structure analysis of the ADD domain of ATRX revealed that it contains a PHD zinc-finger domain packed against a GATA-like zinc finger. Same structure is also found in the DNMT3 DNA methyltransferases and DNMT3L [, , ].
