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Human Set and Ring associated (SRA) domain of UHRF1 bound to methylated DNA

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PDB Code 3CLZ Target Class ubiquitin family Target UHRF1 Alias FLJ21925, hNP95, ICBP90, MGC138707, Np95, RNF106 Disease Area/Function cancer, chromatin and epigenetics, signalling Date Deposited Mar 20 2008 Authors Walker JR, Avvakumov GV, Xue S, Dong A, Bountra C, Weigelt J, Arrowsmith CH, Edwards AM, Bochkarev A, Dhe-Paganon S Related Structure 3DB4, 3DB3, 3FL2

About this structure

Epigenetic inheritance in mammals is characterized by high-fidelity replication of CpG methylation patterns during development1,2. UHRF1 (also known as ICBP90 in humans and Np95 in mouse)3 is an E3 ligase important for the maintainance of global and local DNA methylation in vivo4,5. It’s preferential affinity for hemi-methylated over symmetrically-methylated DNA via its Set and Ring Associated (SRA) domain6 and its association with the maintenance DNA methyltransferase 1 (DNMT1) suggests a role in replication of the epigenetic code4,5,7. Here we report the 1.7 Å crystal structure of the apo SRA domain of human UHRF1 and a 2.2 Å structure of its complex with hemi-methylated DNA, revealing a novel reading mechanism for methylated CpG sites. The SRA-DNA complex has several dramatic structural features including a binding pocket that accommodates the 5-methyl-cytosine which is flipped out of the duplex DNA. Two specialized loops reach through the resulting gap in the DNA from both the major and 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.

References

  1. Holliday, R. & Pugh, J. E. DNA modification mechanisms and gene activity during development. Science 187, 226-232 (1975).
  2. Razin, A. & Riggs, A. D. DNA methylation and gene function. Science 210, 604-610 (1980).
  3. Unoki, M., Bronner, C. & Mousli, M. A concern regarding the current confusion with the human homolog of mouse Np95, ICBP90/UHRF1. Radiat Res 169, 240-244 (2008).
  4. Sharif, J. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908-912 (2007).
  5. Bostick, M. et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760-1764 (2007).
  6. Unoki, M., Nishidate, T. & Nakamura, Y. ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 23, 7601-7610 (2004).
  7. Achour, M. et al. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene 27, 2187-2197 (2008).