Biochemical Properties of MutL, a DNA Mismatch Repair Endonuclease-猫眼课题宝

DOI：

10.5772/23758

发表时间：

2011-09

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作者：

K. Fukui;A. Shimada;H. Iino;R. Masui;S. Kuramitsu

DNA错配修复（MMR）是最广泛保守的DNA修复系统之一，它修复主要由DNA聚合酶在复制过程中的错误产生的错配碱基（Friedberg, et al., 2006; Iyer, et al., 2006; Kunkel, et al., 2005; Morita, et al., 2010）。 MMR 将复制保真度提高了 20 至 400 倍（Schaaper，1993）。 MMR 基因的突变和表观遗传沉默导致人类遗传性非息肉病性结肠癌以及散发性肿瘤（Fishel, et al., 1995；Fishel, et al., 1994；Kane, et al., 1997；Leach, et al., 1993；Modrich, et al., 1996；Suter, et al., 2004），表明了其重要性。这个修复系统。迄今为止，两种类型的 MMR 机制已被阐明：一种是真核生物和大多数细菌所采用的（图 1A 和 B）（Modrich，2006），另一种是大肠杆菌和其他 γ-变形菌所特有的（图 1C）（Modrich 等，1996）。两类错配修复的基本机制和所需蛋白质相对相似。错配可被细菌 MutS 同二聚体、真核 MutS（MSH2-MSH6 异二聚体）或 MutS（MSH2-MSH3 异二聚体）识别（Acharya, et al., 2003, Drotschmann, et al., 2002, Gradia, et al., 1997, Gradia, et al., 1999, Lamers, et al.等人，2000；McCulloch 等人，2003；Obmolova 等人，2000；Tachiki 等人，2000）。随后，细菌 MutL 同二聚体或真核 MutL（分别是人类和酵母中的 MLH1-PMS2 和 MLH1-PMS1 异二聚体）被募集到不匹配的 DNA 中以刺激下游事件（Acharya 等人，2003 年；Kadyrov 等人，2006 年）。两种MMR机制之间最大的区别在于“链歧视”系统。尽管构成错配的两个碱基都是规范的，但 MMR 需要确定要修复哪个碱基。在真核生物和大多数细菌中，MMR 通过识别新合成链中的链不连续性来指导修复错配双链体中含有错误的链（Kadyrov, et al., 2006；Kadyrov, et al., 2007；Larrea, et al., 2010；Modrich, 2006）。前导链和滞后链的末端被认为充当辨别信号。另一方面，大肠杆菌 MMR 读取新合成链的限制位点处不存在甲基化（Iyer, et al., 2006; Kunkel, et al., 2005; Larrea, et al., 2010）。在位点特异性 DNA 甲基化酶（例如大肠杆菌 Dam 甲基化酶（Schlagman 等人）

DNA mismatch repair (MMR) is one of the most widely conserved DNA repair systems, which repairs mismatched bases generated mainly by the error of DNA polymerases during replication (Friedberg, et al., 2006, Iyer, et al., 2006, Kunkel, et al., 2005, Morita, et al., 2010). MMR increases the replication fidelity by 20 to 400-fold (Schaaper, 1993). Mutations and epigenetic silencing in MMR genes cause human hereditary nonpolyposis colon cancers as well as sporadic tumors (Fishel, et al., 1995, Fishel, et al., 1994, Kane, et al., 1997, Leach, et al., 1993, Modrich, et al., 1996, Suter, et al., 2004), indicating the significance of this repair system. To date, two types of MMR mechanisms have been clarified: one is employed by eukaryotes and most bacteria (Fig. 1A and B) (Modrich, 2006) and the other is specific to Escherichia coli and other -proteobacteria (Fig. 1C) (Modrich, et al., 1996). The fundamental mechanism and the required proteins in the two types of MMRs are relatively similar to each other. A mismatch is recognized by the bacterial MutS homodimer, eukaryotic MutS (MSH2-MSH6 heterodimer), or MutS (MSH2-MSH3 heterodimer) (Acharya, et al., 2003, Drotschmann, et al., 2002, Gradia, et al., 1997, Gradia, et al., 1999, Lamers, et al., 2000, McCulloch, et al., 2003, Obmolova, et al., 2000, Tachiki, et al., 2000). Subsequently, the bacterial MutL homodimer or eukaryotic MutL (MLH1-PMS2 and MLH1-PMS1 heterodimers in humans and yeast, respectively) is recruited to the mismatched DNA to stimulate downstream events (Acharya, et al., 2003, Kadyrov, et al., 2006). The largest difference between the two types of MMR mechanisms is in the “strand discrimination” system. Although both bases constituting the mismatch are canonical, MMR needs to identify which base is to be repaired. In eukaryotes and most bacteria, MMR directs the repair to the error-containing strand of the mismatched duplex by recognizing the strand discontinuities in the newly synthesized strand (Kadyrov, et al., 2006, Kadyrov, et al., 2007, Larrea, et al., 2010, Modrich, 2006). The termini of leading and lagging strands are thought to serve as discrimination signals. On the other hand, E. coli MMR reads the absence of methylation at the restriction site in the newly synthesized strand (Iyer, et al., 2006, Kunkel, et al., 2005, Larrea, et al., 2010). Before the site-specific DNA methylase (e.g., E. coli Dam methylase (Schlagman, et

Biochemical Properties of MutL, a DNA Mismatch Repair Endonuclease

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