Nucleases in DNA repair span a growing number of prokaryotic, archeal and eukaryotic exo- and endonucleolytic enzymes with specialized roles in different repair pathways. DSB, double strand break; ICL, interstrand crosslink; MBL, metallo-
1. Introduction
All living organisms must struggle to maintain genomic integrity and long-term stability in the face of the lesions that are constantly inflicted upon the genome by environmental factors, e.g., genotoxic chemicals, UV light, ionizing radiation (IR), and endogenous factors, e.g., during DNA replication. These various DNA lesions (or injuries) encompass a bewildering array of chemical and physical modifications to the DNA structure that must be repaired to preserve the faithful maintenance of the genome. A prevalent class of DNA lesion consists of a break across both DNA strands, termed double strand break (DSB) (Fig. 1 and Table 1). Only of endogenous origin, about 50 DSBs have been calculated to occur per human cell division (Vilenchik and Knudson 2003). Many of these DSBs are generated by IR, reactive oxygen species, and DNA replication across a nick (Ma, J.L. et al. 2003). If left unrepaired, DSBs can cause dire effects such as gene loss during cell division, chromosomal translocations, increased mutation rates, and carcinogenesis (Khanna and Jackson 2001). The various cellular mechanisms that are collectively referred to as DNA repair include DNA damage detection (or sensing), binding and recruitment of specialized protein complex machinery to the site of damage, signaling, initiation of repair, repair, and resolution of the lesion (Fig. 1).
Central to all DNA repair processes are nucleases, enzymes and enzyme complexes that can cleave DNA either in a sugar specific fashion (e.g., DNA and RNA nucleases) or in a sugar unspecific fashion (Marti and Fleck 2004). Nucleases can be further divided into exonucleases, which remove nucleotides from a free 5’ or 3’ end, and endonucleases, which hydrolyze internal phosphodiester bonds without the requirement for a free end. DNA nucleases, which can cleave single stranded (ss) or double stranded (ds) DNA, cleave a phosphodiester bond between a deoxyribose and a phosphate group, thus producing one cleavage product with a 5’ terminal phosphate group and another product with a 3’ terminal hydroxyl group.
Two kinds of DNA lesions, double strand breaks (DSBs) and interstrand crosslinks (ICLs) (Fig. 1), are significantly dependent on the timely action of DNA nucleases, since the initiating step in the repair pathways of DSBs and ICLs often consists of an exonucleolytic or endonucleolytic cleavage that exposes the substrate for the next DNA repair activity. Without the action of a nuclease, the DNA lesion would stay unrepaired because of chemically inaccessible or sterically blocked DNA intermediates. Therefore, nucleases are an integral part of the cellular mechanisms that have evolved to handle DNA damage. Indeed, quality repair mechanisms that strive to reconstitute the undamaged, original DNA structure imply that DNA lesion repair, after the initial nucleolytic processing, requires additional factors, minimally DNA synthesis and ligation, but it also can involve a complex sequence of molecular events.
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DSB | Non-homologous end joining (NHEJ) | Mre11 | PP2B |
Artemis | MBL | ||
DSB | Homologous recombination (HR) | Mre11 | PP2B |
DSB | Microhomology-mediated end joining | Mre11 | PP2B |
ICL | Repair of interstrand crosslinks (ICL) | SNM1A/B | MBL |
DSBs are repaired in human cells mainly by two alternative mechanisms, non-homologous end joining (NHEJ) and homologous recombination (HR) (Fig. 1). While HR occurs mostly in S/G2 phase (Takata et al. 1998), when a sister chromatid is available to provide a template to replace the damaged nucleotides, NHEJ, which does not require a template (Ma, J.L. et al. 2003), is prevalent during G1/early S phase (Takata et al. 1998). The sequential steps necessary for NHEJ comprise synapsis (the protein-mediated structure whereby the two ends of a DSBs are tethered, or held together in close proximity, to allow successful repair), end resection (catalyzed by nucleases), DNA synthesis, and ligation (Fig 1). HR requires too an initial exonucleolytic step that consists of the resection of both strands at the DSB end, thus preparing them for the invasion of the neighboring, intact chromatid DNA (Fig. 1). DNA synthesis, branch migration, Holliday junction resolution, and ligation of remaining nicks, are the next steps needed to complete DNA repair by HR. Regardless of the repair pathway used, an exonucleolytic step is always required to provide the DNA substrates for the subsequent repair processes.
A second class of DNA lesions, ICL, can be generated exogenously by mono- or bifunctional alkylating agents (crosslinkers), IR, and endogenously by the collapse of replication forks. A crosslink at a replication fork leads to stalling, since the individual DNA strands can no longer be unwound for DNA synthesis. Repair of an ICL-induced stalled replication fork can be achieved by the series of steps outlined in Fig. 1. Here again, the initial, critical step is an endonucleolytic cleavage catalyzed by DNA nucleases, which helps convert the stalled fork to a DSB-like lesion that is susceptible to repair.
In the following we will survey two families of DNA nucleases that play significant roles in one or various processes involved in the repair of DSB and ICL lesions, from the indispensable initiation of end resection of broken DNA ends to other specialized DNA repair processes such as those in ICL repair. These families, which are structurally and functionally related, are the metallo-
2. Nucleases of the MBL and PP2B families in DNA repair
Here we summarize current knowledge on two related families of DNA repair nucleases that share significant similarity at the topology, fold structure, active site composition and metal-ion binding: the metallo-
Both the MBL and PP2B families of nucleases belong to the two-metal-ion-dependent nucleases (Yang 2010), an operational class that encompasses the largest variety of tertiary folds and the broadest range of biological outcomes among the nucleases. The defining feature of these enzymes is the absolute dependence for catalytic competence of an active center with two metal ions, one of which acts by polarizing the substrate phosphoester whereas the second is more commonly associated with the stabilization of the nascent negative charge on the leaving group. Given the enormous variety of folds and substrate structures, this simple principle (that this class of nucleases are unified by their two-metal-ion dependence) provides an appropriate framework for discussing their structural and mechanistic properties (Yang 2010). Nucleases from the MBL and PP2B families have been implicated in two specific repair pathways of DNA lesions, the repair of DSBs by non-homologous end joining (NHEJ) and the repair of interstrand crosslinks (ICL) (Fig. 1 and Table 1).
2.1. Metallo-β -lactamase fold nucleases
The metallo-
The MBL family encompasses a large number of enzymes with hydrolytic activities toward a variety of different substrates and, less frequently, oxidorreductases. The best-known hydrolytic MBLs include the zinc-dependent
The
Metallo- |
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I | II | III | IV | ||||
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SNM1A | FTV |
LT |
AN |
ILHTG |
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SNM1/Pso2 | IVV |
LS |
AN |
ILHTG |
||
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SNM1B/Apollo | IAV |
LS |
AN |
ILYTG |
||
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SNM1C/Artemis | ISI |
LS |
AG |
VLYTG |
||
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CPSF-73 | IML |
IS |
AG |
LLYTG |
||
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UlaG | VCV |
AT |
AF |
LYHSG |
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BLM | VLV |
IT |
KG |
ILVCG |
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A | B | C | |||||
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SNM1A | LYL |
E |
IPT |
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SNM1/Pso2 | LYL |
E |
IPT |
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SNM1B/Apollo | LYL |
D |
VPI |
|||
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SNM1C/Artemis | VYL |
F |
YPN |
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CPSF-73 | LII |
A |
ILV |
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EUKARYA | CPSF-73 | Human | 2I7T (Mandel et al. 2006) |
CPSF-100 (Ydh1p) | Yeast | 2I7X (Mandel et al. 2006) | |
ARCHEA | CPSF subunit PH1404 |
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3AF5 (Nishida et al. 2010) |
CPSF homolog |
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2XR1 (Mir-Montazeri et al. 2011) | |
EUBACTERIA | TTHA0252 |
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2DKF (Ishikawa et al. 2006) |
EF2904 |
|
2AZ4 (MSDG) |
Even though there is no known crystal structure for DNA nucleases of the
In Archea, homologs of the
The first
2.1.1. SNM1A/Pso2
In yeast, Pso2 levels are strictly conserved with less than one mRNA molecule per cell; however, upon induction of interstrand crosslinks (ICLs) the amount of
becomes dramatically upregulated (Wolter et al. 1996; Lambert et al. 2003). Accordingly,
Of the higher eukaryotic homologs of Pso2, the slightly greater sequence identity and comparatively longer N terminus of SNM1A makes it the closest in terms of sequence and domain structure (Fig. 3). This similarity suggested that SNM1A could be, too, the closest vertebrate ortholog to yeast Pso2, and therefore exhibit similar functions in ICL repair. Even though current evidence partly supports that proposal, one must caution that ICL processing is significantly more complex in vertebrates than in yeast, in part because of the concourse of two complexes [XPF-ERCC1 (De Silva et al. 2000, 2002) and Fanconi anemia proteins (Niedernhofer et al. 2005; Taniguchi and D'Andrea 2006)] that are lacking in yeast. Like yeast Pso2, SNM1A shows 5’- to 3’-exonuclease activity on ssDNA (slightly preferred) and dsDNA and importantly can complement
2.1.2. SNM1B/APOLLO
Apollo is termed after Artemis (SNM1C; see section 2.1.3) because of their structural and gene sequence similarities (Demuth et al. 2004) (Fig. 2-3). There are two splice variants of
2.1.3. SNM1C/ARTEMIS
Artemis is a third vertebrate
An area that is hotly debated concerns the activation of Artemis upon DNA damage. Early studies suggested that the activation of Artemis depended on its phosphorylation by DNA PKcs, on the basis that Artemis has eleven Ser and Thr residues that are phosphorylatable in vitro (Ma, Y. et al. 2002; Niewolik et al. 2006). More recently, it has been shown that DNA cleavage by Artemis could be facilitated by a hypothetical DNA conformational change upon DNA PKcs autophosphorylation (Goodarzi et al. 2006; Yannone et al. 2008; Gu et al. 2010). Another element of discussion is whether Artemis has one single active site that is responsible for both the exonucleolytic and the endonucleolytic activity, or there are two separate, though partially overlapping, active sites for each of these activities. This question is based on the fact that mutants of Artemis impair only the endonuclease activity but have no consequences for Artemis exonuclease activity (Ma, Y. et al. 2002; Pannicke et al. 2004); strikingly, not even an Asp736 mutant of Artemis, a mutant that losses activity in all other SNM1 family members, compromises the 5’- to 3’-exonuclease activity. The latter, and the fact that two (even partially) separated active sites could coexist in a
Efforts to clarify which roles does Artemis play in DNA repair have provided two sound answers. First, failure of Artemis deficient cells to show defects upon exposure to ICL inducing chemicals dispels a potential role for Artemis in the repair of ICL lesions. Instead, Artemis nuclease activity has been shown to be involved in the repair of a subgroup of DSBs (10–15%) produced by IR that contain covalently modified ends refractory to direct repair by other nucleases (Riballo et al. 2004; Wang, J. et al. 2005; Darroudi et al. 2007). The processing by Artemis of those ‘blocked’ DSBs so that they become accessible to downstream DNA repair machinery would be fitting with the known ability of Artemis-DNA PKcs to process 5’ or 3’ overhangs, hairpins, loops, gaps, or flaps, within DNA (Ma, Y. et al. 2005), as well as oxidation lesions at DNA ends (Povirk et al. 2007). In fact, DNA PKcs has been demonstrated to recruit Artemis to DSB sites, especially in heterochromatin, where DNA PKcs could modify the DNA structure so as to facilitate cleavage by Artemis (Goodarzi et al. 2006). At DSBs, Artemis collaborates with ATM to promote DSB repair by two different pathways, NHEJ at G0/G1 phase and HR at G2 phase (Goodarzi et al. 2006).
2.2. Protein phosphatase fold nucleases (Mre11)
The most prominent DNA nuclease of the protein phosphatase 2B (PP2B) fold is Mre11 (Meiotic recombination 11) (Gueguen et al. 2001), which is one of the central nucleases for the repair of DSBs by the non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways. Phylogenetic analyses show that Mre11 is conserved across the tree of life, likely because of its vital functionality in DNA repair. Mre11 contains five conserved motifs (shared with some structurally related polymerase small subunits), including a two-metal-ion-binding site that has a strong preference for manganese (Gueguen et al. 2001) and is essential for catalysis in the archeal, yeast, and human enzymes. At least in vitro, Mre11 exhibits the following enzymatic activities: ssDNA endonuclease, dsDNA 3’- to 5’-exonuclase, DNA hairpin cleaving (Hopfner et al. 2001), and activation of DNA checkpoint kinase (ATM in humans, Tel1 in yeast) (Williams, R.S. et al. 2008). Mn2+ is required for all these activities, and interaction of Mre11 with Rad50 is necessary for dsDNA 3’- to 5’-exonuclease and cleaving DNA hairpins (Hopfner et al. 2001; Ghosal and Muniyappa 2005; Williams, R.S. et al. 2008). Besides, Mre11 has been observed to participate in 5’ to 3’ end resection of DSBs in vivo (Williams, R.S. et al. 2007), although the precise mechanism remains to be completely elucidated. A current working model involves other enzymes with nuclease or helicase activity in addition to Mre11, like Sae2, Exo1, Dna2, or Sgs1 (Zhu et al. 2008). The cooperation between these enzymes is supported by the observation of a reduced 5’- to 3’-exonucleolytic activity in cells lacking Exo1 and a complete ablation of this activity when Exo1, Sae2, and the MRX complex are all absent (Zhu et al. 2008). It appears that Mre11, together with Sae2, initiates DSB resection by facilitating trimming of 5’ ends, which can then be degraded by Exo1 or Dna2, in collaboration with the Sgs1 helicase, thus generating long single-stranded overhangs (Mimitou and Symington 2008).
As many other DNA processing enzymes, Mre11 is part of a multisubunit complex whose core is composed of four subunits, two subunits of Mre11 and two of Rad50 (Table 1). In this four-subunit MR complex, Mre11 acts as the nuclease engine, whereas Rad50 contributes localization and tethering specific functions. In eukaryotic organisms, as opposed to the simpler archeal and bacterial MR complex, there is a third subunit associated with Mre11 and Rad50, Nbs1 (or Xrs2 in yeast). Nbs1 is an integral part of the eukaryotic complex, which is named MRN (in yeast, MRX) (Hopfner et al. 2001). The MRN complex participates in various DNA repair processes such as in DNA damage detection, HR (Williams, R.S. et al. 2008), telomere maintenance, or checkpoint signaling, meiotic recombination, NHEJ and MMEJ (Lammens et al. 2011). Through its capacity to activate the ATM kinase, the MRN complex participates in the cell cycle (Lammens et al. 2011).
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ARCHEA | Mre11:Rad50 |
|
3QKR (Williams, G.J. et al. 2011) |
Mre11 |
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3DSD, 3DSC (Williams, R.S. et al. 2008) | |
Mre11 |
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1II7 (Hopfner et al. 2001) | |
Mre11-3 |
|
1S8E (Arthur et al. 2004) | |
EUBACTERIA | Mre11:Rad50 |
|
3QF7, 3QG5 (Lammens et al. 2011) |
Mre11 |
|
2Q8U (Das et al. 2010) |
Several crystal structures of Mre11 in several functionally relevant complexes have been solved in two extremophilic microorganisms: the Archea
Similarly to other nucleases of the MBL fold, archeal and human Mre11 are homodimeric enzymes. Two chains of Mre11 assemble in a homodimer with an interface composed of
As explained above, the presence of two metal ions is an absolute requirement for the nuclease activity of Mre11. In
In
The MR complex from
Telomere ends are a special class of DSBs, and in this context it has been shown that yeast Mre11 (
3. Structural and catalytic parallels
The MBL and PP2B families have a number of significant similarities at different, functionally relevant levels, and therefore many parallels can be drawn between the two nuclease families, structurally and catalytically. First, the core of either fold consists of
Several crystal structures of archeal Mre11 alone and in complex with DNA reveal a conserved homodimer with a tertiary structure and active sites that are reminiscent to those of
This array of similarities between Mre11 and the
4. Nucleases at the heart of DNA repair complexes
Protein complexes, rather than isolated proteins, carry out the immense majority of cellular functions, and the intricate processes of DNA repair are no exception. Even though there are nucleases that perform catalysis in the absence of physically associated protein partners, the highly regulated and exquisitely orchestrated process of DNA repair requires protein multisubunit complexes able to sense inputs and effect biological outcomes via the nucleosome engine subunit. A conspicuous example is the MRN complex, which has been described as an analog computer molecular machine.
All of the
As has been pointed out above (Section 2), Mre11 acts in the context of multisubunit complexes with Rad50 and/or Nbs1/Xrs2 (MR and MRN/MRX complexes, respectively) that provide expanded functionality in the recognition and tethering of DSBs and the sensing of cellular stress signals via its non-nuclease subunits. These extra capabilities are essential to target DSBs and avoid wasteful scanning and/or enzymatic processing by Mre11. Small-angle x-ray scattering (SAXS) and analytical ultracentrifuge (AUC) experiments have provided compelling evidence that the MR complex is a heterotetramer formed by two subunits each of Mre11 and Rad50; corroborative evidence of the subunit composition of the MR complex has been obtained by electron microscopy (EM) (Hopfner et al. 2001). Furthermore, the tethering of DNA by the MRX complex has been shown by atomic force microscopy (AFM) (Williams, R.S. et al. 2008). Perhaps the most convincing evidence is the direct observation of the interaction surfaces between Mre11 with the nucleotide-binding domain of Rad50 (Fig. 4), and of the coiled coil segment of Rad50 and an Mre11-derived peptide, both captured by x-ray crystallography from the archeal and the eubacterial MR complexes (Williams, G.J. et al. 2011).
Apart from its role as the nucleolytic engine of the MRN complex, Mre11 acts jointly with other nucleases in what may be described as a functional cooperation. A chief example of this comes from the observation made in yeast that both Mre11 and another exonuclease, Exo1, are both required for the efficient initiation and processivity of resection at specific DSBs generated during meiosis (Hodgson et al. 2011). Loss of function of either Mre11 or Exo1 causes severe delay in resection, therefore suggesting that Mre11 and Exo1 are the major nucleases involved in creating the resection tracts typical of meiotic recombination (Hodgson et al. 2011).
5. Evolution of DNA repair nucleases
MBL fold nucleases involved in DNA repair have most likely evolved from precursor enzymes with the capacity to act upon RNA substrates, which are widespread across the tree of life and include enzymes that can recognize either sequence features, structure, or combined sequence-structure signatures on RNA substrates. Changing the substrate specificity from RNA to DNA should have been easily achieved during evolution, as the same fold scaffolds have been proven to catalyze either reaction. Many of these MBL RNases utilize inserted domains to assist recognition and binding of RNA molecules, which are large and very densely charged molecules. One outstanding example concerns RNases from the MBL superfamily, which often possess a
PP2B nucleases, like Mre11, are also widespread across the tree of life and have been identified in Bacteria, Archea, and Eukarya. Crystal structures of the eubacterial and archeal enzymes are available in the Protein Data Bank for comparison, and they have been shown to be of different length while maintaining all of the conserved key residues for catalysis, as well as the identity of the catalytic metal ion (manganese). Therefore, it is quite plausible that there existed an Mre11-like enzyme in the last universal common ancestor (LUCA) of all extinct life forms with, potentially, similar roles in DSB repair and maintenance of genome integrity. Further support for this idea is derived from the clear assumption that the selection pressure for sophisticated and efficient DNA repair machinery for LUCA must have been even stronger than at present.
6. Disease states and mutations in nucleases
There is a plethora of mutation studies in MBL and PP2B nucleases carried out in model organisms that can be related to human pathophysiology linked to DNA repair and genome stability. These disease-associated mutations provide a wealth of information on function, specificity, and redundancy of the DNA repair nucleases.
Among the nucleases from the MBL family, a well-known syndrome is radiation sensitive severe combined immunodeficiency (RS-SCID), a disease condition that arises from defects in Artemis and is truly the result of impaired function of Artemis in DNA repair and in V(D)J recombination (Dominski 2007). Another striking example comes from patients with Hoyeraal-Hreidarsson (HH) syndrome, a severe form of
The PP2B family protein Mre11 has a vital role across phylogenetically diverse organisms ranging from Bacteria to vertebrates, on the basis of its crucial role in DNA repair. Well-established links between
7. Conclusions and future outlook
There are many standing issues in the field of DNA repair nucleases whose elucidation awaits further research. Some of these issues include the complete biochemical and structural characterization of DNA nucleases of the MBL fold family, which are known to play key roles in DNA repair but which have thus far proved hard to reveal their substrate specificities (e.g., ssDNA versus dsDNA), activities (e.g., controversies over the 3’-5’ and 5’-3’ exonuclease activities of Artemis), or even the requirement for post-translational modifications (such as DNA PKcs mediated phosphorylation of Artemis). In protein phosphatase nucleases, the best-known example is archeal and eukaryotic Mre11 and the architecture of the MRN complex. There, one crucial aspect is to decipher how the MRN complex processes all its inputs and delivers a comprehensive functional outcome. In more applied science, there is always the wide-ranging and crucial question of how can the tremendous amount of basic science results be put to clinical use. In DNA repair, the identification of mutations that cause, or predispose, to acquire certain diseases must advance to the point that early diagnosis becomes feasible for many. Cures to these diseases may be far into the future, but the current and near future research is providing sure steps toward this much-longed end.
Acknowledgments
The authors will like to acknowledge financial support from grants PET2008_0101 and BFU2010-22260-C02-02 from the Spanish Ministry of Science and Innovation (MICINN) to MCV. FJF and MLE were supported by the MICINN grant PET2008-0101 and a fellowship (ME-517217) from the Spanish Ministry of Education, respectively. MLE acknowledges the support of the Ph.D. program in Biochemistry, Molecular Biology and Biomedicine of the Universidad Complutense de Madrid (UCM).
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