The function of the DNMT3L and UHRF1 proteins: Two critical co-regulations of DNA methylation in mammals

The primary repository for heritable biological information in all living cells is found in the sequence of DNA molecules. Eukaryotic cells, however, carry a second layer of so called epigenetic information which is written in through chemical modifications of the DNA and of the chromatin in a way that does not change the primary DNA sequence. Such epigenetic information is key for cellular function. My primary focus of study was DNA methylation which is an essential epigenetic process in mammals. Despite this importance, the mechanisms by which DNA methylation patterns are established and maintained are currently unclear. To gain a better understanding of these processes, I have undertaken a study of two proteins required for proper DNA methylation: DNMT3L and UHRF1. I have shown that DNMT3L serves to stimulate the activity of DNMT3A by reorganizing DNMT3A homomeric complexes into discrete DNMT3A:DNMT3L complexes with increased substrate binding characteristics (Chapter 1)(Kareta et al., 2006), that mutation of DNMT3L in humans can lead to intergenic hypomethylation and a loss of methylation at telomeres, implicating DNMT3L in telomere maintenance (El-Maarri et al., 2009), and that DNMT3L is able to read the histone landscape to help direct DNA methylation (Chapter 3, Appendix 2). I have also shown that UHRF1, a protein required for maintenance of DNA methylation is also capable of recognizing the chromatin landscape (Chapter 4). Understanding the function of these two proteins has served to further our knowledge of the greater mechanisms which underlie DNA methylation, a mark essential for human health and development.