Increasing role of UHRF1 in the reading and inheritance of the epigenetic code as well as in tumorogenesis

Abstract

Epigenetic mechanisms such as DNA methylation and histone posttranslational modifications, allow cells to maintain the phenotype throughout successive mitosis. UHRF1 plays a major role in the inheritance of some epigenetic marks from mother cells to daughter cells due to its particular structural domains. The originality of UHRF1 lies in the fact that it can read epigenetic marks and recruit the enzymes that catalyze the same epigenetic mark. The SRA domain senses the presence of a methylated cytosine on one DNA strand allowing the recruitment of DNMT1, which methylates the cytosine on the newly synthesized DNA. The recently identified tudor domain of UHRF1 senses the presence of methylated histone H3 conducting UHRF1 to recruit histone methyltransferases. Recent studies deciphering the relationships between some of the structural domains of UHRF1 provides new insights on the reading of the epigenetic code over a larger portion of histone tail than usually expected. Furthermore, latest developments highlights that UHRF1 is one of the proteins which is able to directly connect DNA methylation to histone epigenetic marks. This paper reviews the principles how UHRF1 acts as an epigenetic reader and discusses the properties of UHRF1 to be a biomarker as well as a therapeutic target.

Keywords: Cancer; DNA methylation; DNA methyltransferase 1; DNMT1; Epigenetic; Histones; PARP; Poly (ADP-ribose) polymerase; RING; Really Interesting New Gene; SET and RING-finger associated domain; SRA; TTD; UHRF1; VEGF; tandem tudor domain; ubiquitin-like containing PHD and RING finger domains, 1; vascular endothelial growth factor.