This week we profile a recent publication in Molecular Cell from the
laboratory of Dr. Rachel Klevit (pictured) at the University of Washington.
Can you provide a brief overview of your lab’s current research focus?
An overarching theme of my lab is to understand guardians of the cell. We are currently focussed on two broad areas: guardians of the genome and guardians of the proteome. In the former category, the modification of nucleosomal histones with ubiquitin is emerging as a mark that is involved in the DNA damage response, transcriptional regulation, and maintenance of epigenetic marks. In the second category are the small heat shock proteins, which are a cell’s first responders in times of stress. These enigmatic protein chaperones are known to be involved in a growing number of human diseases and syndromes, especially neurodegenerative disease, cardiomyopathies, and cataract.
What is the significance of the findings in this publication?
This publication reports on the structural mechanism by which methylated CpG motifs are maintained following DNA replication. Surprisingly, the DNA methylation reaction requires action by a ubiquitin E3 ligase, UHRF1. We show how a small domain in UHRF1 couples the recognition of a CpG site that requires methylation to the modification of histone H3 with ubiquitin, which in turn recruits the DNA methyltransferase, DNMT1. We show that known cancer-associated mutations in this domain of UHRF1 uncouple the recognition and modification reactions.
What are the next steps for this research?
A full understanding of this important system will require full reconstitution of the active complex and structural investigation at the atomic level. The high level of dynamics that are intrinsic to the system make this a challenging goal.
This research was funded by:
This work was funded by NIH NIGMS (National Institute for General Medical Sciences.
