Alhosin et al. Journal of Experimental & Clinical Cancer Research 2011, 30:41 http://www.jeccr.com/content/30/1/41 Page 3 of 10 Figure 1 Schematic representation of UHRF1 with the structural domains facing either DNA or histones. Abbreviation: UBL, Ubiquitin-like domain; TTD, cryptic Tandem Tudor Domain; PHD, Plant Homeo Domain; SRA, Set and Ring Associated; RING, Really Interesting New Gene. The major partners of UHRF1, namely Tat-Interactive Protein of 60 kDA (Tip60), DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a (G9a) and Histone DeAcetylase (HDAC1) are also depicted. these clinical studies show that immuno-histochemical staining of UHRF1 may improve the specificity and sen- sitivity of current tests for cancer diagnosis. These stu- dies also emphasize that over-expression of UHRF1 might be involved in the establishment of aberrant his- tone code and altered DNA methylation patterns. The consequences of UHRF1 over-expression are cell contact inhibition loss [41] and inhibition of TSGs expression, such as CDKN2A and RASSF1 [42]. Furthermore, very recently, it was shown that UHRF1 down-regulation in p53 containing and deficient cancer cells induced cell cycle arrest in G2/M and caspase-8-dependent apoptosis [43]. This is consistent with previous studies showing that down-regulation of UHRF1 leads to cell growth inhibition [44-46]. UHRF1 is characterized by the presence of several structural domains, some facing DNA and others facing histones (Figure 1). Among them, one of the most amazing domain is undoubtedly the SRA domain (Set and Ring Associated) which, in vertebrates, is found only in the UHRF family [35]. Thanks to this domain, UHRF1 interacts with histone deacetylase 1 (HDAC1) and can bind to methylated promoter regions of various TSGs, including p16INK4A and p14ARF [44]. Moreover, we have shown that UHRF1, via the SRA domain, associates with DNA methyltransferase 1 (DNMT1) to form a couple cooperating in the duplication of the DNA methylation patterns but other domains of UHRF1 could also be involved [26,47-49]. The mechanism of DNA methylation pattern duplication, involves the SRA domain which is able to detect the hemi-methylated state of the DNA that occurs after the synthesis of the new DNA strand [50-52]. This domain behaves as a “hand” with a palm which holds the methylated cyto- sine, after that two “fingers” have flipped the methylated cytosine out from the DNA helix into the major DNA groove. The flipped methylated cytosine allows UHRF1 to be anchored at the hemi-methylated site to give the time necessary for DNMT1 to methylate the newly synthesized DNA strand [26,53], thus ensuring the maintenance of the DNA methylation patterns through successive cell divisions. Altogether, these observations show that immediately after DNA replication which generates hemi-methylated strands, UHRF1 is recruited with DNMT1 and/or likely DNMT3a and DNMT3b, in order to perpetuate gene repression, and particularly that of TSGs in cancer cells. Recently, two novel and interesting partners of UHRF1, namely Tip60 (Tat-Interactive Protein) and HAUSP (Herpes virus-Associated Ubiquitin Specific Protease) have been identified [54,55]. Indeed, we showed that Tip60 is present in the same macromolecu- lar complex as UHRF1, DNMT1, and HDAC1. Tip60 is a histone acetyltransferase with specificity toward lysine 5 of histone H2A (H2AK5) [54]. Interestingly, we observed that UHRF1 down-regulation correlated with