Linear double-stranded DNA-specific nicking endonucleases. 1Structural analyses have revealed that AP endonucleases, retrotransposon-targeting endonucleases, and DNase I are closely related to each other. 2
1. Introduction
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
In both MMR systems, a nicking endonuclease plays a central role in the strand discrimination mechanism. In eukaryotes and most bacteria, MutL homologues are thought to incise the discontinuous strand to introduce the entry or termination point of the excision reaction. In
Although
2. Structure of the C-terminal endonuclease and N-terminal ATPase domains of MutL
The C-terminal domain of MutL endonucleases contains two highly conserved sequence motifs (Fig. 3). One of them is the DQHA(x)2E(x)4E motif, which is essential for the nicking endonuclease activity (Fukui, et al., 2008, Kadyrov, et al., 2006). Aspartic acid and histidine residues in this motif are expected to coordinate one or two metal ions to catalyze the nicking reaction (Kosinski, et al., 2008, Pillon, et al., 2010, Yang, 2008). The other is the zinc-binding motif CPHGRP (Kosinski, et al., 2008), which is not essential for the nicking endonuclease activity but is required for the
structures, which are dimeric molecules, resemble that of the
The N-terminal ATPase domain of MutL contains a single ATP-binding motif per subunit just like other GHKL superfamily proteins (Ban, et al., 1998, Guarné, et al., 2001). Unlike the C-terminal domain, the amino acid sequence of the N-terminal ATPase domain of the MutL endonuclease is highly homologous to that of
of the N-terminal domain. As with the MutL endonuclease, the crystal structure of the N-terminal domain of human PMS2 has been reported (Fig. 5B) (Guarné, et al., 2001). Intriguingly, the N-terminal domain of PMS2 bound to ATPγS even in the absence of the N-terminal domain of MLH1, which is the only report concerning ATP binding by a monomeric GHKL superfamily protein. However, it is expected that in the presence of the MLH1 subunit, ATP binding induces dimerization of the N-terminal domains. In line with this notion, a direct observation using atomic force microscopy suggested that ATP binding causes dimerization of the N-terminal domain in yeast MutLα (Sacho, et al., 2008).
3. ATP modulates the nicking endonuclease activity of MutL
The effect of ATP on the biochemical properties of the MutL endonuclease has been examined using the bacterial MutL endonuclease as a model molecule.
In order to detect a nicking endonuclease activity, the covalently closed circular form of plasmid DNA is often used as a substrate (Fukui, et al., 2007). A nicking endonuclease activity converts the closed circular form into an open circular form of the plasmid DNA that can be easily separated from the closed circular form and the linearized form by agarose gel electrophoresis. Mn2+ facilitates the mismatch-, MutS-, clamp-, and clamp loader-independent incision of the closed circular form by non-sequence-specific MutL endonuclease activity (Duppatla, et al., 2009, Fukui, et al., 2008, Kadyrov, et al., 2006, Mauris, et al., 2009).
When
Interestingly, AMPPNP and a mismatch facilitated the stable interaction between
Mauris and Evans reported the detailed biochemical experiment on
4. The N-terminal ATPase domain stimulates the endonuclease activity of the C-terminal domain
As described in the previous section, the endonuclease activity of MutL is modulated by ATP binding and/or hydrolysis. Because the ATP binding and endonuclease active sites are located in the N- and C-terminal domains, respectively, the interdomain interaction between them had been expected. This prediction was verified by the recent experiment using recombinant N- and C-terminal domains from
It is expected that this interdomain interaction is involved in the ATPase cycle-dependent regulatory mechanism of MutL. Direct observation using atomic force microscopy has suggested the possible ATP binding-induced association of the N-terminal domain to the C-terminal domain (Fig. 6, middle) (Sacho, et al., 2008). Such an approach may reflect the interdomain interaction that is required for stimulating the nicking endonuclease activity. However, as mentioned above, ATP binding suppresses and ATP hydrolysis promotes the nicking endonuclease activity (Duppatla, et al., 2009, Fukui, et al., 2008, Pillon, et al., 2010). Therefore, ATP hydrolysis may create a tighter contact of the N-terminal domain with the C-terminal domain than that created by ATP binding (Fig. 6, right). Such a tight contact may stimulate the nicking endonuclease activity. Further studies are necessary to clarify whether and how ATP hydrolysis affects the structure and function of MutL endonuclease.
5. Interaction with a sliding clamp directs the MutL-dependent incision to the discontinuous strand
In the above sections, we reviewed the possible regulatory mechanism that assures the mismatch-specific nicking endonuclease activity of MutL. We also have to consider a regulatory mechanism that directs the nicking endonuclease activity of MutL to the error-containing strand of the mismatched duplex. Mismatch itself has no signal to discriminate which base is incorrect (Friedberg, et al., 2006).
Additionally, another question has arisen: how does MutL sense the strand discontinuity that is remote from the MutL incision site? In an
Interestingly,
6. Bacterial MutL is a homodimeric nicking endonuclease
Crystal structures of
Enzyme | Cellular function | Substrate | Biological unit | References |
N-type nicking endonucleases (e.g., N. | Host defense (Artificial) | Asymmetric sequence | Monomer | (Higgins, et al., 2001, Roberts, et al., 2003, Xu, et al., 2001, Yunusova, et al., 2006, Zheleznaya, et al., 2009) |
V-type nicking endonucleases (e.g., | DNA repair4 and other | Methylated DNA | Monomer | (Tsutakawa, et al., 1999, Tsutakawa, et al., 1999) |
Type I DNA topoisomerases (e.g., | Various DNA transactions | Supercoiled DNA | Monomer | (Kirkegaard, et al., 1978) |
Retrotransposon-targeting endonucleases1 (e.g., L1 endonuclease) | Targeting of retrotransposon | Target sequence | Monomer | (Feng, et al., 1996, Feng, et al., 1998, Maita, et al., 2007, Weichenrieder, et al., 2004) |
Bovine DNase I1 | Host defense | Non-specific | Monomer | (Suck, et al., 1988) |
DNA repair4 | GATC site | Monomer | (Ban, et al., 1998) | |
DNA repair4 | DNA strand with bulky adducts | Monomer | (Nazimiec, et al., 2001) | |
DNA repair4 | Deaminated DNA | Monomer | (Dalhus, et al., 2009) | |
AP endonucleases1 (e.g., human APE1) | DNA repair4 | DNA with abasic sites | Monomer | (Hosfield, et al., 1999, Mol, et al., 2000) |
Host defense | Non-specific | Dimer | (Franke, et al., 1998, Franke, et al., 1999) | |
Bacterial MutL3 (e.g., | DNA repair4 | DNA strand with mismatched bases | Dimer | (Namadurai, et al., 2010, Pillon, et al., 2010) |
The homodimeric structure of bacterial MutL prompts the question of how the symmetric homodimer generates asymmetric nicking products. As with eukaryotic MutLα, the asymmetry would be derived from the nature of the heterodimer. Eukaryotic MutLα has a single catalytic site for the endonuclease activity. On the other hand, bacterial MutL contains two catalytic sites that are apparently equivalent to each other. It may be possible that bacterial MutL dissociates from the substrate DNA before the catalysis of the second strand incision because of its low velocity, or that the binding of the product to the one subunit induces a non-productive binding mode of the substrate to the other subunit. Alternatively, as proposed by Namadurai
7. Conclusion
In this chapter, the biochemical properties of MutL endonucleases are reviewed, with an emphasis on their regulatory mechanisms. The regulatory mechanism needs to ensure both mismatch- and daughter-strand-specific incisions. The ATPase cycle-dependent conformational and functional changes of the MutL endonucleases are expected to play a central role in these mechanisms. Since the ATPase cycle-dependent conformational change would involve the rearrangement of the interaction between the N- and C-terminal domains, the structural analysis of full-length MutL is urgently required. For the structural analysis, MutL homologues from some thermophilic bacterium may be suitable because of the lack of flexible interdomain linker region as well as their extreme thermostability. However, the interdomain linker region plays a significant role in the in vitro function of eukaryotic MutLα (Gorman, et al., 2010). Therefore, it is necessary to carefully judge whether the obtained information is universal among all MutL endonucleases.
Acknowledgments
This work was partly supported by Grant-in-Aid for Scientific Research 20570131 (to R. M.) from the Ministry of Education, Science, Sports and Culture of Japan.
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