We are pleased to welcome Dr Roberto Bellelli from The Francis Crick Institute, to present at CRUK Barts Centre on Tuesday 5th November.
The seminar is entitled: ‘Mechanisms of genetic and epigenetic instability: Pol Epsilon and beyond’
Genomic instability is a major hallmark of cancer and understanding its nature and origins may provide avenues for patient-tailored therapies. The plasticity of cancer cells is also suggestive of epigenetic mechanisms at the heart of cancer development, which add a further level of complexity to the challenge of tumour heterogeneity. Indeed, epigenetic instability, due to alteration of DNA methylation, histone post-translational modifications and/or chromatin remodelers has been observed in most malignancies and is now considered a bona fide hallmark of cancer. Despite this, the interplay between genetic and epigenetic instability remains to be clarified, particularly in the context of DNA replication, which represents an opportunity for both genome and epigenome deregulation.
A paradigm in this area of research is mammalian DNA polymerase Epsilon and its smallest subunits, POLE3-POLE4, which I have discovered promotes both efficient replication initiation and facilitates Histone H3-H4 recycling at the replication fork to maintain genetic and epigenetic stability, respectively. Through the generation of a mouse knock-out for Pole4 and the identification of POLE1 mutations in patients affected by IMAGe syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal Hypoplasia and genital anomalies) and immunodeficiency, I have described the mechanistic consequences of Pol Epsilon instability in genome maintenance, mammalian development and tumorigenesis. More recently I discovered that POLE3-POLE4 interacts with and chaperones H3-H4 at the replication fork to maintain epigenome integrity and described the molecular determinants of this activity.
This work suggests the critical need to dissect in vitro and in vivo the relative contribution of these functions and emphasizes a possible interplay, yet to be identified, with histone chaperones, chromatin remodelers and other replisome components. Identification of these players and their crosstalk in the context of chromatin replication will be of fundamental importance to understand the basis of epigenetic inheritance in mammals and its pathological alteration in cancer.
The seminar will be held in the Lister and Young Seminar Room, 12:30-13:30.
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