Abstract
DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is an epigenetic mark that needs to be faithfully replicated during mitosis in order to maintain cell phenotype during successive cell divisions. This epigenetic mark is located on the 5′-carbon of the cytosine mainly within cytosine–phosphate–guanine (CpG) dinucleotides. DNA methylation is asymmetrically positioned on both DNA strands, temporarily generating a hemi-methylated state after DNA replication. Hemi-methylation is a particular status of DNA that is recognized by ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) through its SET- (Su(var)3-9, Enhancer-of-zeste and Trithorax) and RING-associated (SRA) domain. This interaction is considered to be involved in the recruitment of DNMT1 to chromatin in order to methylate the adequate cytosine on the newly synthetized DNA strand. The UHRF1/DNMT1 tandem plays a pivotal role in the inheritance of DNA methylation patterns, but the fine-tuning mechanism remains a mystery. Indeed, because DNMT1 experiences difficulties in finding the cytosine to be methylated, it requires the help of a guide, i.e., of UHRF1, which exhibits higher affinity for hemi-methylated DNA vs. non-methylated DNA. Two models of the UHRF1/DNMT1 dialogue were suggested to explain how DNMT1 is recruited to chromatin: (i) an indirect communication via histone H3 ubiquitination, and (ii) a direct interaction of UHRF1 with DNMT1. In the present review, these two models are discussed, and we try to show that they are compatible with each other.
Highlights
The origin of these two upheavals in DNA methylation patterns is not yet fully elucidated, but might find a beginning of an explanation in the altered communication between ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) and DNA methyltransferase 1 (DNMT1) [18,19], which is the matter of the present review
We previously suggested that the discrepancies might come from the species-specific difference [59]; it was later shown that the interacting domain in mouse DNMT1 was a region encompassing aa 291–601 corresponding to the RFTS domain [114]
We suggest that the UHRF1/DNMT1 tandem slides along the newly synthesized
Summary
DNA methylation mainly occurs on cytosine–phosphate–guanine (CpG) dinucleotides, and almost. A global hypomethylation is observed in cancer cells, which promotes the expression of oncogenes and aggravates tumorigenesis by inducing genomic instability [16,17] The origin of these two upheavals in DNA methylation patterns is not yet fully elucidated, but might find a beginning of an explanation in the altered communication between ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) and DNA methyltransferase 1 (DNMT1) [18,19], which is the matter of the present review. Two-thirds of the primary sequence of UHRF1 contributes to these structural domains, suggesting that this protein fulfils multiple important roles One of these roles is the link between the histone code and DNA methylation. The crystal structure revealed that the RFTS domain directly localization associates with the(aa catalytic domain, The crystal revealed that the RFTS therebystructure exhibiting auto-inhibition abilitydomain [96]. directly associates with the catalytic domain, thereby exhibiting auto-inhibition ability [96]
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