PR-SET7, 也称SET8、KMT5a , 是现今发现唯一能够特异性单甲基化H4K20的赖氨酸甲基转移酶(Lysine methyltransferase, KMT)。在细胞周期不同时相PR-SET7的含量处于波动之中, 主要受泛素连接酶调节。PR-SET7与细胞增殖密切相关, 其催化的组蛋白H4K20单甲基化修饰在DNA复制、染色体固缩及细胞周期检验点激活中发挥重要调控作用。PR-SET7缺失将导致DNA损伤, 细胞周期阻滞, 甚至发生细胞凋亡。而且, PR-SET7可以调节ERa、Wnt、p53等多种基因的转录, 进而影响相应基因的表达。PR-SET7为个体发育所必需, 并参与了基因组印记的形成。另外, PR-SET7还能促进肿瘤的发生和转移, 有望成为肿瘤治疗的新靶点。文章主要从PR-SET7的结构、对组蛋白修饰的调节、在细胞周期、基因转录过程中的调控, 以及其在个体发育和肿瘤发生中的作用等方面综述了PR-SET7的研究进展。
PR-SET7 (also named SET8 or KMT5a) is a sole lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20me1) in higher eukaryotes. The abundance of PR-SET7 is dynamically mediated by the distinct E3 ubiquitin ligases in different cell cycle phases. PR-SET7 is closely related to the regulation of cell proliferation, and the H4K20me1 catalyzed by PR-SET7 has been implicated in regulating the diverse biological processes, including DNA replication, chromosome condensation and the activation of DNA replication checkpoints. Loss of PR-SET7 results in mas-sive DNA damage, cell cycle arrest and induction of apoptosis. In addition, PR-SET7 involves in regulating the transcrip-tion of several genes, such as ERa, Wnt and p53. PR-SET7 is also essential for individual development and partici-pates in the formation of genomic imprinting. Moreover, PR-SET7 has been reported to promote tumorigenesis and metastasis, suggesting that PR-SET7 may be a potential target for cancer treatment. In this review, we focus on analyzing the structure of PR-SET7 and factors influencing histone modification on regulation of PR-SET7, and discuss the mechanisms by which PR-SET7 modulates cell-cycle progression, gene transcription, individual development and tumorigenesis.
[1] Strahl BD, Allis CD. The language of covalent histone modifications. Nature, 2000, 403(6765): 41-45.
[2] Taverna SD, Li HT, Ruthenburg AJ, Allis CD, Patel DJ. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol, 2007, 14(11): 1025-1040.
[3] Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, Pillus L, Reinberg D, Shi Y, Shiekhattar R, Shilatifard A, Workman J, Zhang Y. New nomenclature for chromatin-modifying enzymes. Cell, 2007, 131(4): 633-636.
[4] Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature, 2000, 406(6796): 593-599.
[5] Dillon SC, Zhang X, Trievel RC, Cheng XD. The SET-domain protein superfamily: protein lysine methyltrans-ferases. Genome Biol, 2005, 6(8): 227.
[6] Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y, Chuikov S, Valenzuela P, Tempst P, Steward R, Lis JT, Allis CD, Reinberg D. PR-Set7 is a nucleosome-specific methyltransferase that modifies ly-sine 20 of histone H4 and is associated with silent chro-matin. Mol Cell, 2002, 9(6): 1201-1213.
[7] Oda H, Okamoto I, Murphy N, Chu J, Price SM, Shen MM, Torres-Padilla ME, Heard E, Reinberg D. Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development. Mol Cell Biol, 2009, 29(8): 2278-2295.
[8] Rice JC, Nishioka K, Sarma K, Steward R, Reinberg D, Allis CD. Mitotic-specific methylation of histone H4 Lys 20 follows increased PR-Set7 expression and its localization to mitotic chromosomes. Genes Dev, 2002, 16(17): 2225-2230.
[9] Fang J, Feng Q, Ketel CS, Wang HB, Cao R, Xia L, Erd-jument-Bromage H, Tempst P, Simon JA, Zhang Y. Puri-fication and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr Biol, 2002, 12(13): 1086-1099.
[10] Abbas T, Shibata E, Park J, Jha S, Karnani N, Dutta A. CRL4Cdt2 regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation. Mol Cell, 2010, 40(1): 9-21.
[11] Xiao B, Jing C, Kelly G, Walker PA, Muskett FW, Frenkiel TA, Martin SR, Sarma K, Reinberg D, Gamblin SJ, Wilson JR. Specificity and mechanism of the histone methyltransferase Pr-Set7. Genes Dev, 2005, 19(12): 1444-1454.
[12] Qian C, Zhou MM. SET domain protein lysine methyltransferases: Structure, specificity and catalysis. Cell Mol Life Sci, 2006, 63(23): 2755-2763.
[13] Guo HB, Guo H. Mechanism of histone methylation cata-lyzed by protein lysine methyltransferase SET7/9 and ori-gin of product specificity. Proc Natl Acad Sci USA, 2007, 104(21): 8797-8802.
[14] Centore RC, Havens CG, Manning AL, Li JM, Flynn RL, Tse A, Jin JP, Dyson NJ, Walter JC, Zou L. CRL4Cdt2- mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol Cell, 2010, 40(1): 22-33.
[15] Jørgensen S, Eskildsen M, Fugger K, Hansen L, Larsen MSY, Kousholt AN, Syljuåsen RG, Trelle MB, Jensen ON, Helin K, Sørensen CS. SET8 is degraded via PCNA-coupled CRL4CDT2 ubiquitylation in S phase and after UV irradiation. J Cell Biol, 2011, 192(1): 43-54.
[16] Oda H, Hübner MR, Beck DB, Vermeulen M, Hurwitz J, Spector DL, Reinberg D. Regulation of the histone H4 monomethylase PR-Set7 by CRL4Cdt2-mediated PCNA-dependent degradation during DNA damage. Mol Cell, 2010, 40(3): 364-376.
[17] Brustel J, Tardat M, Kirsh O, Grimaud C, Julien E. Coupling mitosis to DNA replication: the emerging role of the histone H4-lysine 20 methyltransferase PR-Set7. Trends Cell Biol, 2011, 21(8): 452-460.
[18] Wu SM, Wang WP, Kong XD, Congdon
