An Intramolecular Interaction of UHRF1 Reveals Dual Control for Its Histone Association

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2018 Feb 4

PMID 29395786

Citations 23

Authors

Linfeng Gao

Xiao-Feng Tan

Shen Zhang

Tianchen Wu

Zhi-Min Zhang

Hui-Wang Ai

Jikui Song

Affiliations

Soon will be listed here.

Abstract

UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) is one of the essential components of mammalian DNA methylation machinery. Chromatin association of UHRF1 is controlled via an interplay between its intramolecular interaction and dual recognition of histone H3 trimethylated at lysine 9 (H3K9me3) and hemimethylated DNA. Here, we report the crystal structure of the N-terminal tandem Tudor domain (TTD) of UHRF1 in complex with the C-terminal polybasic region (PBR). Structural analysis reveals that PBR binding leads to displacement of the TTD-plant homeodomain (PHD) linker, as well as blockage of the H3K9me3-engaging cage, both of which contribute to a chromatin-occluded UHRF1 conformation. Disruption of the TTD-PBR interaction, which is facilitated by the binding of UHRF1 to hemimethylated DNA or regulatory protein USP7, shifts the UHRF1 conformation toward an open state, allowing for efficient H3K9me3 binding. Together, this study provides structural basis for the allosteric regulation of UHRF1.

Citing Articles

Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response.

Tan L, Yin T, Xiang H, Wang L, Mudgal P, Chen J Nat Commun. 2024; 15(1):8569.

PMID: 39362877 PMC: 11450162. DOI: 10.1038/s41467-024-52902-5.

Oncogenic Roles of UHRF1 in Cancer.

Kim A, Benavente C Epigenomes. 2024; 8(3).

PMID: 39051184 PMC: 11270427. DOI: 10.3390/epigenomes8030026.

Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains (Review).

Song Y, Liu H, Xian Q, Gui C, Xu M, Zhou Y Oncol Lett. 2023; 26(6):542.

PMID: 38020304 PMC: 10660443. DOI: 10.3892/ol.2023.14129.

Natural and Synthetic Anticancer Epidrugs Targeting the Epigenetic Integrator UHRF1.

Ashraf W, Ahmad T, Reynoird N, Hamiche A, Mely Y, Bronner C Molecules. 2023; 28(16).

PMID: 37630248 PMC: 10459542. DOI: 10.3390/molecules28165997.

Refined read-out: The hUHRF1 Tandem-Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3.

Choudalakis M, Kungulovski G, Mauser R, Bashtrykov P, Jeltsch A Protein Sci. 2023; 32(9):e4760.

PMID: 37593997 PMC: 10464304. DOI: 10.1002/pro.4760.

References

Liang C, Zhan B, Yoshikawa Y, Haas W, Gygi S, Cohn M . UHRF1 is a sensor for DNA interstrand crosslinks and recruits FANCD2 to initiate the Fanconi anemia pathway. Cell Rep. 2015; 10(12):1947-56. PMC: 4386029. DOI: 10.1016/j.celrep.2015.02.053. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Liu X, Gao Q, Li P, Zhao Q, Zhang J, Li J . UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9. Nat Commun. 2013; 4:1563. DOI: 10.1038/ncomms2562. View

Fang J, Cheng J, Wang J, Zhang Q, Liu M, Gong R . Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition. Nat Commun. 2016; 7:11197. PMC: 4822050. DOI: 10.1038/ncomms11197. View

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M . Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature. 2008; 455(7214):818-21. DOI: 10.1038/nature07249. View

Xie S, Jakoncic J, Qian C . UHRF1 double tudor domain and the adjacent PHD finger act together to recognize K9me3-containing histone H3 tail. J Mol Biol. 2011; 415(2):318-28. DOI: 10.1016/j.jmb.2011.11.012. View

Cheng J, Yang Y, Fang J, Xiao J, Zhu T, Chen F . Structural insight into coordinated recognition of trimethylated histone H3 lysine 9 (H3K9me3) by the plant homeodomain (PHD) and tandem tudor domain (TTD) of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) protein. J Biol Chem. 2012; 288(2):1329-39. PMC: 3543016. DOI: 10.1074/jbc.M112.415398. View

Ma H, Chen H, Guo X, Wang Z, Sowa M, Zheng L . M phase phosphorylation of the epigenetic regulator UHRF1 regulates its physical association with the deubiquitylase USP7 and stability. Proc Natl Acad Sci U S A. 2012; 109(13):4828-33. PMC: 3323953. DOI: 10.1073/pnas.1116349109. View

10.

Afonine P, Grosse-Kunstleve R, Echols N, Headd J, Moriarty N, Mustyakimov M . Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr D Biol Crystallogr. 2012; 68(Pt 4):352-67. PMC: 3322595. DOI: 10.1107/S0907444912001308. View

11.

Goll M, Bestor T . Eukaryotic cytosine methyltransferases. Annu Rev Biochem. 2005; 74:481-514. DOI: 10.1146/annurev.biochem.74.010904.153721. View

12.

Law J, Jacobsen S . Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010; 11(3):204-20. PMC: 3034103. DOI: 10.1038/nrg2719. View

13.

Nishiyama A, Yamaguchi L, Sharif J, Johmura Y, Kawamura T, Nakanishi K . Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature. 2013; 502(7470):249-53. DOI: 10.1038/nature12488. View

14.

Jin W, Liu Y, Xu S, Yin W, Li J, Yang J . UHRF1 inhibits MDR1 gene transcription and sensitizes breast cancer cells to anticancer drugs. Breast Cancer Res Treat. 2009; 124(1):39-48. DOI: 10.1007/s10549-009-0683-8. View

15.

Rajakumara E, Wang Z, Ma H, Hu L, Chen H, Lin Y . PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression. Mol Cell. 2011; 43(2):275-284. PMC: 4691841. DOI: 10.1016/j.molcel.2011.07.006. View

16.

Bird A . DNA methylation patterns and epigenetic memory. Genes Dev. 2002; 16(1):6-21. DOI: 10.1101/gad.947102. View

17.

Mistry H, Tamblyn L, Butt H, Sisgoreo D, Gracias A, Larin M . UHRF1 is a genome caretaker that facilitates the DNA damage response to gamma-irradiation. Genome Integr. 2010; 1(1):7. PMC: 2914011. DOI: 10.1186/2041-9414-1-7. View

18.

Hu L, Li Z, Wang P, Lin Y, Xu Y . Crystal structure of PHD domain of UHRF1 and insights into recognition of unmodified histone H3 arginine residue 2. Cell Res. 2011; 21(9):1374-8. PMC: 3193472. DOI: 10.1038/cr.2011.124. View

19.

Karagianni P, Amazit L, Qin J, Wong J . ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol Cell Biol. 2007; 28(2):705-17. PMC: 2223417. DOI: 10.1128/MCB.01598-07. View

20.

Qin W, Wolf P, Liu N, Link S, Smets M, La Mastra F . DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res. 2015; 25(8):911-29. PMC: 4528052. DOI: 10.1038/cr.2015.72. View