Journal
NATURE
Volume 455, Issue 7214, Pages 822-U13Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature07273
Keywords
-
Categories
Funding
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut
- Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co., Inc
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- Canadian Cancer Society
Ask authors/readers for more resources
Epigenetic inheritance in mammals is characterized by high- fidelity replication of CpG methylation patterns during development(1,2). UHRF1 ( also known as ICBP90 in humans and Np95 in mouse)(3) is an E3 ligase important for the maintenance of global and local DNA methylation in vivo(4,5). The preferential affinity of UHRF1 for hemi- methylated DNA over symmetrically methylated DNA by means of its SET and RING- associated ( SRA) domain(6) and its association with the maintenance DNA methyltransferase 1 ( DNMT1) suggests a role in replication of the epigenetic code(4,5,7). Here we report the 1.7 angstrom crystal structure of the apo SRA domain of human UHRF1 and a 2.2 angstrom structure of its complex with hemi- methylated DNA, revealing a previously unknown reading mechanism for methylated CpG sites ( mCpG). The SRA - DNA complex has several notable structural features including a binding pocket that accommodates the 5-methylcytosine that is flipped out of the duplex DNA. Two specialized loops reach through the resulting gap in the DNA from both the major and the minor grooves to read the other three bases of the CpG duplex. The major groove loop confers both specificity for the CpG dinucleotide and discrimination against methylation of deoxycytidine of the complementary strand. The structure, along with mutagenesis data, suggests how UHRF1 acts as a key factor for DNMT1 maintenance methylation through recognition of a fundamental unit of epigenetic inheritance, mCpG.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available