基因组的遗传稳定性是维持正常的细胞复制、增殖和分化的关键。外源因素和内源因素造成的DNA损伤及其修复失败, 是各种遗传疾病发生的根本原因。表观遗传调控(包括DNA甲基化、组蛋白修饰和非编码RNA)在DNA损伤修复和细胞周期调控方面发挥着重要的作用, 也是维持基因组稳定性的基础。酵母作为单细胞真核生物, 是最早开展表观遗传学研究的物种之一, 特别是在DNA损伤修复和异染色质形成等方面的研究, 为揭示遗传稳定性的本质提供了理论依据。国际上前期以酵母为模式生物研究表观遗传学的报道主要集中于组蛋白修饰领域; 近期利用裂殖酵母作为模式生物研究RNAi指导的组蛋白修饰也有了一定的进展。文章以酵母作为模式生物, 论述了表观遗传修饰在维持基因组遗传稳定性中的研究进展、作用机制和今后的发展趋势。
Genomic integrity is crucial for normal cell replication, proliferation and differentiation. DNA lesions resulted from exogenous and endogenous factors will lead to genomic instability, and consequently the cause for various diseases. Epigenetic regulation (including DNA methylation, histone modifications and non-coding RNA) plays important roles in DNA lesion repair and cell cycle regulation as well as maintaining the genetic integrity. The yeast, a type of single cell eu-karyotic organism, is an ideal model for the researches of epigenetics, especially in the area of DNA lesion repair and the formation of heterochromatin. Previous researches on epigenetics were mainly focus on histone modifications. Recent re-searches have observed that non-coding RNAs are able to direct the cytosine methylation and histone modifications that are related to gene expression regulation. This paper discuss the mechanism, research progress and future development of epi-genetics in maintaining the genomic integrity, using the yeast as a model.
[1] Rouse J, Jackson SP. Interfaces between the detection, signaling, and repair of DNA damage. Science, 2002, 297 (5581): 547-551.
[2] Costa FF. Non-coding RNAs, epigenetics and complexity. Gene, 2008, 410 (1): 9-17.
[3] Wolffe AP, Matzke MA. Epigenetics: Regulation through repression. Science, 1999, 286(5439): 481-486.
[4] Rando OJ. Global patterns of histone modifications. Curr Opin Genet Dev, 2007, 17 (2): 94-99.
[5] 张永彪, 褚嘉佑. 表观遗传学与人类疾病研究进展. 遗传, 2005, 27(3): 466-472.
[6] Brownell JE, Zhou JX, Ranalli T, Kobayashi R, Edmondson DG, Roth SY, Allis CD. Tetrahymena histone acetyltrans- ferase A: A homolog to yeast Gcn5p linking histone acetyla- tion to gene activation. Cell, 1996, 84 (6): 843-851.
[7] Juranek SA, Rupprecht S, Postberg J, Lipps HJ. SnRNA and heterochromatin formation are involved in DNA exci- sion during macronuclear development in stichotrichous ciliates. Eukaryotic Cell, 2005, 4 (11): 1934-1941.
[8] Liu Y, Taverna SD, Muratore TL, Shabanowitz J, Hunt DF, Allis CD. RNAi-dependent H3K27 methylation is required for heterochromatin formation and DNA elimination in Tetrahymena. Genes Dev, 2007, 21 (12): 1530-1545.
[9] Huisinga KL, Elgin SCR. Small RNA-directed hetero-chromatin formation in the context of development: What flies might learn from fission yeast. Biochim Biophys Acta, 2009, 1789 (1): 3-16.
[10] Shi YJ, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. Histone demethylation mediated by the nuclear arnine oxidase homolog LSD1. Cell, 2004, 119 (7): 941-953.
[11] Auriche C, Di Domenico EG, Ascenzioni F. Budding yeast with human telomeres: A puzzling structure. Biochimie, 2008, 90(1): 108-115.
[12] Schoeftner S, Blasco MA. A 'higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs. Embo J, 2009, 28 (16): 2323-2336.
[13] Ting AH, McGarvey KM, Baylin SB. The cancer epige-nome-components and functional correlates. Genes Dev, 2006, 20 (23): 3215-3231.
[14] Bernstein E, Allis CD. RNA meets chromatin. Genes Dev, 2005, 19 (14): 1635-1655.
[15] Colot V, Rossignol JL. Eukaryotic DNA methylation as an evolutionary device. Bioessays, 1999, 21(5): 402-411.
[16] Antequera F, Tamame M, Villanueva JR, Santos T. DNA Methylation in the Fungi. J Biol Chem, 1984, 259 (13): 8033-8036.
[17] Kouzminova E, Selker EU. dim-2 encodes a DNA methyl-transferase responsible for all known cytosine methylation in Neurospora. Embo J, 2001, 20(15): 4309-4323.
[18] Altaf M, Saksouk N, Cote J. Histone modifications in re-sponse to DNA damage. Mutat Res, 2007, 618(1-2): 81-90.
[19] Fillingham J, Keogh MC, Krogan NJ. gamma H2AX and its role in DNA double-strand break repair. Biochem Cell Biol, 2006, 84 (4): 568-577.
[20] Foster ER, Downs JA. Histone H2A phosphorylation in DNA double-strand break repair. Febs J, 2005, 272 (13): 3231-3240.
[21] Neilson C, Santos-Rosa H, Bannister A, Kouzarides T. Chromatin modifications and their function. Febs J, 2006, 273: 22-22.
[22] Kouzarides T. Chromatin modifications and their function. Cell, 2007, 128 (4): 693-705.
[23] Morrison AJ, Kim JA, Person MD, Highland J, Xiao J, Wehr TS, Hensley S, Bao Y, Shen J, Collins SR, Weissman JS, Delrow J, Krogan NJ, Haber JE, Shen X. Mec1/Tel1 phosphorylation of the INO80 chromatin remodeling complex influences DNA damage checkpoint responses. Cell, 2007, 130 (3): 499-511.
[24] Wu WH, Wu CH, Ladurner A, Mizuguchi G, Wei D, Xiao H, Luk E, Ranjan A, Wu C. N Terminus of Swr1 Binds to histone H2AZ and provides a platform for subunit assem-bly in the chromatin remodeling complex. J Biol Chem, 2009, 284 (10): 6200-6207.
[25] Doyon Y, Selleck W, Lane WS, Tan S, Cote J. Structural and functional conservation of the NuA4 histone acetyl-transferase complex from yeast to humans. Mol Cell Biol, 2004,
