| Structural highlights
Function
[UHRF1_MOUSE] Multidomain protein that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification. Specifically recognizes and binds hemimethylated DNA at replication forks via its YDG domain and recruits DNMT1 methyltransferase to ensure faithful propagation of the DNA methylation patterns through DNA replication. In addition to its role in maintenance of DNA methylation, also plays a key role in chromatin modification: through its tudor-like regions and PHD-type zinc fingers, specifically recognizes and binds histone H3 trimethylated at 'Lys-9' (H3K9me3) and unmethylated at 'Arg-2' (H3R2me0), respectively, and recruits chromatin proteins. Enriched in pericentric heterochromatin where it recruits different chromatin modifiers required for this chromatin replication. Also localizes to euchromatic regions where it negatively regulates transcription possibly by impacting DNA methylation and histone modifications. Has E3 ubiquitin-protein ligase activity by mediating the ubiquitination of target proteins such as histone H3 and PML. It is still unclear how E3 ubiquitin-protein ligase activity is related to its role in chromatin in vivo. May be involved in DNA repair.[1] [2] [3] [4] [5] [6] [7] [8]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Maintenance methylation of hemimethylated CpG dinucleotides at DNA replication forks is the key to faithful mitotic inheritance of genomic methylation patterns. UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is required for maintenance methylation by interacting with DNA nucleotide methyltransferase 1 (DNMT1), the maintenance methyltransferase, and with hemimethylated CpG, the substrate for DNMT1 (refs 1 and 2). Here we present the crystal structure of the SET and RING-associated (SRA) domain of mouse UHRF1 in complex with DNA containing a hemimethylated CpG site. The DNA is contacted in both the major and minor grooves by two loops that penetrate into the middle of the DNA helix. The 5-methylcytosine has flipped completely out of the DNA helix and is positioned in a binding pocket with planar stacking contacts, Watson-Crick polar hydrogen bonds and van der Waals interactions specific for 5-methylcytosine. Hence, UHRF1 contains a previously unknown DNA-binding module and is the first example of a non-enzymatic, sequence-specific DNA-binding protein domain to use the base flipping mechanism to interact with DNA.
The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix.,Hashimoto H, Horton JR, Zhang X, Bostick M, Jacobsen SE, Cheng X Nature. 2008 Oct 9;455(7214):826-9. Epub 2008 Sep 3. PMID:18772888[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Muto M, Kanari Y, Kubo E, Takabe T, Kurihara T, Fujimori A, Tatsumi K. Targeted disruption of Np95 gene renders murine embryonic stem cells hypersensitive to DNA damaging agents and DNA replication blocks. J Biol Chem. 2002 Sep 13;277(37):34549-55. Epub 2002 Jun 25. PMID:12084726 doi:http://dx.doi.org/10.1074/jbc.M205189200
- ↑ Bonapace IM, Latella L, Papait R, Nicassio F, Sacco A, Muto M, Crescenzi M, Di Fiore PP. Np95 is regulated by E1A during mitotic reactivation of terminally differentiated cells and is essential for S phase entry. J Cell Biol. 2002 Jun 10;157(6):909-14. Epub 2002 Jun 10. PMID:12058012 doi:http://dx.doi.org/10.1083/jcb.200201025
- ↑ Citterio E, Papait R, Nicassio F, Vecchi M, Gomiero P, Mantovani R, Di Fiore PP, Bonapace IM. Np95 is a histone-binding protein endowed with ubiquitin ligase activity. Mol Cell Biol. 2004 Mar;24(6):2526-35. PMID:14993289
- ↑ Unoki M, Nishidate T, Nakamura Y. ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene. 2004 Oct 7;23(46):7601-10. PMID:15361834 doi:10.1038/sj.onc.1208053
- ↑ Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA, Shinga J, Mizutani-Koseki Y, Toyoda T, Okamura K, Tajima S, Mitsuya K, Okano M, Koseki H. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007 Dec 6;450(7171):908-12. Epub 2007 Nov 11. PMID:17994007 doi:http://dx.doi.org/10.1038/nature06397
- ↑ Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science. 2007 Sep 21;317(5845):1760-4. Epub 2007 Aug 2. PMID:17673620 doi:10.1126/science.1147939
- ↑ Nady N, Lemak A, Walker JR, Avvakumov GV, Kareta MS, Achour M, Xue S, Duan S, Allali-Hassani A, Zuo X, Wang YX, Bronner C, Chedin F, Arrowsmith CH, Dhe-Paganon S. Recognition of multivalent histone states associated with heterochromatin by UHRF1. J Biol Chem. 2011 Apr 13. PMID:21489993 doi:10.1074/jbc.M111.234104
- ↑ Qin W, Leonhardt H, Spada F. Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1. J Cell Biochem. 2011 Feb;112(2):439-44. doi: 10.1002/jcb.22998. PMID:21268065 doi:http://dx.doi.org/10.1002/jcb.22998
- ↑ Hashimoto H, Horton JR, Zhang X, Bostick M, Jacobsen SE, Cheng X. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature. 2008 Oct 9;455(7214):826-9. Epub 2008 Sep 3. PMID:18772888 doi:10.1038/nature07280
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