| 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] DPPA3_MOUSE Primordial germ cell (PGCs)-specific protein involved in epigenetic chromatin reprogramming in the zygote following fertilization. In zygotes, DNA demethylation occurs selectively in the paternal pronucleus before the first cell division, while the adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Participates in protection of DNA methylation in the maternal pronucleus by preventing conversion of 5mC to 5hmC: specifically recognizes and binds histone H3 dimethylated at 'Lys-9' (H3K9me2) on maternal genome, and protects maternal genome from TET3-mediated conversion to 5hmC and subsequent DNA demethylation. Does not bind paternal chromatin, which is mainly packed into protamine and does not contain much H3K9me2 mark. Also protects imprinted loci that are marked with H3K9me2 in mature sperm from DNA demethylation in early embryogenesis. May be important for the totipotent/pluripotent states continuing through preimplantation development. Also involved in chromatin condensation in oocytogenesis.[9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
Ubiquitin-like with PHD and RING finger domain-containing protein 1 (UHRF1)-dependent DNA methylation is essential for maintaining cell fate during cell proliferation. Developmental pluripotency-associated 3 (DPPA3) is an intrinsically disordered protein that specifically interacts with UHRF1 and promotes passive DNA demethylation by inhibiting UHRF1 chromatin localization. However, the molecular basis of how DPPA3 interacts with and inhibits UHRF1 remains unclear. We aimed to determine the structure of the mouse UHRF1 plant homeodomain (PHD) complexed with DPPA3 using nuclear magnetic resonance. Induced alpha-helices in DPPA3 upon binding of UHRF1 PHD contribute to stable complex formation with multifaceted interactions, unlike canonical ligand proteins of the PHD domain. Mutations in the binding interface and unfolding of the DPPA3 helical structure inhibited binding to UHRF1 and its chromatin localization. Our results provide structural insights into the mechanism and specificity underlying the inhibition of UHRF1 by DPPA3.
Structural basis for the unique multifaceted interaction of DPPA3 with the UHRF1 PHD finger.,Hata K, Kobayashi N, Sugimura K, Qin W, Haxholli D, Chiba Y, Yoshimi S, Hayashi G, Onoda H, Ikegami T, Mulholland CB, Nishiyama A, Nakanishi M, Leonhardt H, Konuma T, Arita K Nucleic Acids Res. 2022 Nov 24:gkac1082. doi: 10.1093/nar/gkac1082. PMID:36420895[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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:https://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:https://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:https://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:https://dx.doi.org/10.1002/jcb.22998
- ↑ Saitou M, Barton SC, Surani MA. A molecular programme for the specification of germ cell fate in mice. Nature. 2002 Jul 18;418(6895):293-300. doi: 10.1038/nature00927. PMID:12124616 doi:https://dx.doi.org/10.1038/nature00927
- ↑ Bortvin A, Eggan K, Skaletsky H, Akutsu H, Berry DL, Yanagimachi R, Page DC, Jaenisch R. Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development. 2003 Apr;130(8):1673-80. PMID:12620990
- ↑ Payer B, Saitou M, Barton SC, Thresher R, Dixon JP, Zahn D, Colledge WH, Carlton MB, Nakano T, Surani MA. Stella is a maternal effect gene required for normal early development in mice. Curr Biol. 2003 Dec 2;13(23):2110-7. PMID:14654002
- ↑ Nakamura T, Arai Y, Umehara H, Masuhara M, Kimura T, Taniguchi H, Sekimoto T, Ikawa M, Yoneda Y, Okabe M, Tanaka S, Shiota K, Nakano T. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol. 2007 Jan;9(1):64-71. doi: 10.1038/ncb1519. Epub 2006 Dec 3. PMID:17143267 doi:https://dx.doi.org/10.1038/ncb1519
- ↑ Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun. 2011;2:241. doi: 10.1038/ncomms1240. PMID:21407207 doi:https://dx.doi.org/10.1038/ncomms1240
- ↑ Liu YJ, Nakamura T, Nakano T. Essential role of DPPA3 for chromatin condensation in mouse oocytogenesis. Biol Reprod. 2012 Feb 14;86(2):40. doi: 10.1095/biolreprod.111.095018. Print 2012 , Feb. PMID:22034526 doi:https://dx.doi.org/10.1095/biolreprod.111.095018
- ↑ Nakamura T, Liu YJ, Nakashima H, Umehara H, Inoue K, Matoba S, Tachibana M, Ogura A, Shinkai Y, Nakano T. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature. 2012 Jun 3;486(7403):415-9. doi: 10.1038/nature11093. PMID:22722204 doi:https://dx.doi.org/10.1038/nature11093
- ↑ Hata K, Kobayashi N, Sugimura K, Qin W, Haxholli D, Chiba Y, Yoshimi S, Hayashi G, Onoda H, Ikegami T, Mulholland CB, Nishiyama A, Nakanishi M, Leonhardt H, Konuma T, Arita K. Structural basis for the unique multifaceted interaction of DPPA3 with the UHRF1 PHD finger. Nucleic Acids Res. 2022 Nov 24:gkac1082. doi: 10.1093/nar/gkac1082. PMID:36420895 doi:https://dx.doi.org/10.1093/nar/gkac1082
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