DNA methylation is essential for mammalian embryonic and post-natal development. Mutations in the de novo DNA methyltransferase DNMT3A, which is expressed as two isoforms, DNMT3A1 and DNMT3A2, cause abnormal brain development in children and clonal hematopoiesis in older individuals. Additionally, DNA methylation patterns are profoundly altered in all human cancers in the absence of mutations in the components of the methylation machinery. We have discovered that a large majority of human tumors overexpress the DNMT3A2 isoform and have determined the cryo-EM structure of this isoform together with its non-catalytically active accessory protein, DNMT3B3 bound to a nucleosome. Unexpectedly, the heterotetrameric complex binds to the acidic patch present on all nucleosomes raising questions as to how specificity of methylation is obtained. The mechanisms responsible for the generation of altered DNA methylation patterns in all human cancers are not understood. We have found profound alterations in the ratios of DNMT3A2 to DNMT3B3 which might be partially responsible for these changes. I will also discuss the development of new drugs and combinations to target abnormal methylation in cancer and present results of small clinical trials in patients to test these approaches.
Peter Jones was born in Cape Town, raised and attended college in Rhodesia (now Zimbabwe), and received his Ph.D. from the University of London. He joined the University of Southern California in 1977, attaining the rank of Professor in 1985 and Distinguished Professor in 1999. He served as Director of the USC Norris Comprehensive Cancer Center between 1993 and 2011. Dr. Jones became Chief Scientific Officer of Van Andel Institute (VAI) in Grand Rapids, Michigan in 2014. His laboratory discovered the effects of 5 azacytidine on cytosine methylation and first established the link between DNA methylation, gene expression and differentiation. He helped pioneer the field of epigenetics, particularly its role in cancer, and helped develop novel cancer therapies. He has published more than 300 scientific papers and received several honors, including two Outstanding Investigator Awards from the NCI. He and Stephen Baylin shared the Kirk Landon Award for Basic Cancer Research from the AACR in 2009 and the Medal of Honor from the American Cancer Society in 2011. Dr. Jones is a past President of the American Association for Cancer Research (AACR) and was elected a Fellow of the American Association for the Advancement of Science in 2009 and a Fellow of the Academy of the AACR in 2013. He was elected a member of the National Academy of Sciences of the USA in 2016, the American Academy of Arts and Sciences in 2017 and received an honorary D.Sc. from Stellenbosch University in 2018.