1. Introduction
DNA is the carrier of genetic information, but is constantly assaulted by endogenous and exogenous genotoxic attacks in all living organisms. If left unrepaired damaged or structurally altered DNA can impede pathways of DNA metabolism and maintenance of genomic stability and lead to cell death or uncontrolled proliferation. Archaea comprise diverse microorganisms that can thrive in harsh environments like hydrothermal vents and acidic hot springs. They can live without sunlight or organic carbon as food, and instead survive on sulfur hydrogen, and other materials that most bacteria and eukaryotes can not metabolize. Considering the extreme environmental niches inhabited by archaeal species, DNA lesions could be massively induced by exposure to hazardous environmental factors, (e.g., ultraviolet, X- and -rays, elevated temperatures and endogenous mutagens, e.g., reactive oxygen/nitrogen species, alkylating agents and toxic metals), and very high rates of potentially mutagenic DNA lesions (deamination, depurination, oxidation by hydrolytic mechanisms, alkylations and subsequent strand breakage) are expected to arise. However, and interestingly, it was demonstrated that the hyperthermophilic crenarchaeota
Like bacteria and eukaryotes, archaeal repair mechanisms seem to include nucleolytic processing of DNA. Consequently, this article sets out to review archaeal DNA nucleases based on current knowledge of sequence, structure and mechanism. We have focused on recent work on several DNA repair nucleases, with a detailed description of substrate preference and cleavage specificity of these archaeal enzymes. Crystal structures, when available, are discussed in the context of biochemical data to outline mechanistic features, such as enzymatic DNA cleavage, DNA binding, and sometimes, although not always, functions. This review stresses the molecular mechanisms which have been conserved throughout evolution with reference to eukaryotic DNA nucleases and, in some cases, to bacterial counterparts. On the other hand, DNA nucleases which appears unique to archaea are emphasized with the aim to describe novel aspects of repair mechanisms.
2. Type 2 Ribonuclease H, a structure-specific DNA repair nuclease
2.1. RNase HII/2: a ubiquitous enzyme
Ribonucleases H (RNases H) catalyse the cleavage of the RNA portion of RNA/DNA hybrid molecules that are ubiquitously present in cells (Stein and Hausen, 1969). RNases H are classified into two major families, type 1 and type 2, based on amino acid sequence identities and distinct biochemical properties. Genes encoding RNases H are found in viruses, archaea, bacteria and eukaryotes and, at least, one RNase H is present within a single cell. Furthermore, type 2 RNases H are more widely distributed than type 1 RNases H in prokaryotic and eukaryotic genomes (Ohtani et al., 1999b). Biological roles, including DNA replication, DNA repair, and transcription have been assigned for these RNases H, as recently reviewed (Cerritelli and Crouch, 2009; Tadokoro and Kanaya, 2009). Here, we report recent progress in the structural and functional characterization of type 2 ribonucleases H (RNase HII/2) presumed to be involved in an excision repair system for the removal of ribose residues with a particular accent on archaeal enzymes.
2.2. RNases HII/2 orthologs
2.2.1. Distribution and amino acid sequence identities
In the process of analysing the 95 sequenced archaeal genomes, type 2 RNases H (RNases HII) have been detected among the five archaeal phyla: Euryarchaeota, Crenarchaeota, Korarchaeota, Thaumarchaeota and Nanoarchaeota. In contrast to the type 1 enzymes, archaeal RNases HII appear universally distributed, and most organisms only contain RNase HII, with the exception of few archaea, such as
Sequence comparison within archaeal RNases HII has revealed a high degree of amino acid sequence identity (Chai et al., 2001; Haruki et al., 1998; Le Laz et al. 2010; Muroya et al., 2001). For instance,
2.2.2. Biochemical characterization
The apparent sequence conservation among RNases HII/2 orthologs would indicate that these enzymes have biochemical properties in common. Interestingly, archaeal RNases HII display activity at alkaline pH (Chai et al., 2001; Haruki et al., 1998; Le Laz et al., 2010), and this property seems to be a hallmark of type 2 RNases H (Chon et al., 2009; Rohman et al., 2008; Rychlik et al., 2010). As first reported by Haruki,
Cleavage specificities for substrates containing single or few ribonucleotides embedded in double-stranded DNA (dsDNA) of type 2 RNases H are now well documented. Such structural substrates can arise
Overall, it appears that Mg-dependent hydrolysis of single or few ribonucleotides embedded in dsDNA along with the unique substrate specificity are a hallmark of type 2 RNases H, implying that key structural elements necessary for activity must be conserved among eukaryotes and prokaryotes.
2.3. Structure and catalysis by RNases HII/2
2.3.1. Overall topology
Structural comparison of three type 2 RNases H from archaea (
2.3.2. Active site, substrate binding and catalytic mechanism
Because the structures of type 2 RNases H contain a common RNase H fold, the catalytic center may be similar among archaea, bacteria and eukaryotes. Comparison of secondary structure among
In the crystal structure of
2.4. Physiological roles for RNases HII/2
Type 2 RNases H are represented in organisms across domains and exhibit a conserved core structure. Moreover, they have been identified as the sole enzymes able to recognise and cleave a single ribonucleotide embedded in dsDNA (Eder and Walder, 1991), thereby contrasting to type 1 RNases H that requires at least four ribonucleotides for cleavage (Ohtani et al., 1999a). As mentioned earlier, single ribonucleotides embedded in dsDNA can arise from external damaging agents (Von Sonntag and Schulte-Frohlinde, 1978), and can occur by intrinsic RNA ligation (Rumbaugh et al., 1997) or erroneous nucleotide incorporation during DNA replication (Nick McElhinny et al., 2010a; Nick McElhinny et al., 2010b). The presence of riboses in DNA has been shown to induce a helical alteration, promoting a B- to A-form transition in DNA (Horton and Finzel, 1996). This result is consistent with the local DNA backbone distortion recently observed in the structure of
3. Endonucleases of the XPF/MUS81 family
DNA repair and replication restart pathways generate a variety of branched structures such as four-way DNA junctions (Holliday junctions, HJs), fork structures and 5'- or 3'-flaps, all of which are substrates for structure-specific endonucleases. Many nucleases that act upon 3'-flap structures belong to the XPF/MUS81 family of proteins, which are present throughout eukarya and archaea but are not found in bacteria. Defects in XPF/MUS81-family members are associated with human disease such as Xeroderma pigmentosum (XPF-ERCC1) (Sijbers et al., 1996) or Fanconi anemia (FANCM) (Meetei et al., 2005).
3.1. Eucaryal members of the XPF/MUS81 family of endonucleases
The human XPF-ERCC1 complex and its counterpart RAD1-RAD10 in
MUS81 complexes are distinct to XPF, and initial work in
Human FANCM was identified thanks to the archaeal ortholog Hef, an XPF/MUS81 family protein featuring a helicase:nuclease fusion (Meetei et al., 2005; Mosedale et al., 2005). The FANCM-FAAP24 complex is a XPF/MUS81 member found in humans (Ciccia et al., 2007) that possesses two separate functions: (i) to recruit the Fanconi anemia core complex to the repair of DNA interstrand crosslinks (Ciccia et al., 2007; Kim et al., 2008; Meetei et al., 2005; Mosedale et al., 2005), and (ii) to facilitate the response to replication stress by the ATR pathway,
3.2. Archaeal members of the XPF/MUS81 family of endonucleases
All archaea encode a protein of the XPF/MUS81/FANCM family of endonucleases except the
3.2.1. Hef
Hef (helicase-associated endonuclease fork-structure DNA) is present only in euryarchaeota and was identified in
restriction endonuclease fold, indicating that Hef nuclease belongs to this restriction endonuclease family (Nishino et al., 2003). Accordingly, the Hef nuclease activity is strictly dependent on Mg2+ or Mn2+ whereas Ca2+ cannot substitute.
The C-terminal fragment of
The substrate specificity for the cleavage activity of the Hef protein is contained in the C-terminal domain as both the C-terminal fragment and the entire Hef protein recognize and cleave nicked, flapped and fork-structured DNAs at the 5’ side of the nicked position.
The N-terminal fragment of
The N-terminal domain of Hef displays a DNA structure-specific helicase activity as the most prominent enhancement of the ATPase activity is observed with fork-structured DNAs. Interestingly
The genetic study of Hef mutant in the euryarchaea
3.2.2. XPF in Crenarcheota
By contrast, the XPF ortholog found in crenarchaeota contains only the C-terminal nuclease domain. The structure of XPF from the crenarchaea
The studies of XPF from
4. The Mre11-Rad50 complex in Archaea
The processing of DNA double strand breaks (DSBs) is a crucial mechanism for genomic integrity. DNA breaks can arise during replication as intermediates in programmed DNA rearrangements including meiosis and immune system development or can be caused by oxidative damages and exposure to ionizing radiations. Double strand break repair (DSBR) is an essential repair pathway in the three domains of life, and plays a major role in the rescue of stalled or collapsed replication forks. In bacteria, DSBs are processed
4.1. Catalytic activities and DSB ends processing
The archaeal homologs of Mre11 and Rad50 were initially identified in
4.2. Structural insight into the Mre11-Rad50 complex
The archaeal MR complex is structurally very similar to their eukaryal counterparts, and has proven very useful for crystallographic and biophysical studies (Arthur et al., 2004; Hopfner et al., 2002a; Hopfner et al., 2001; Hopfner et al., 2000a; Hopfner et al., 2000b; Hopfner et al., 2002b; Williams et al., 2008). Indeed, with the exception of the recent description of the first eubacterial Mre11 nuclease, the bulk of structural data have been obtained from analysis of
The core Mre11-Rad50 complex forms a large globular complex at the root of an elongated coiled-coil structure. The complex exists as a heterotetrameric assembly (M2R2) and the globular head is composed of two Mre11 and two Rad50 ATPase domains, both of which bind DNA (Hopfner et al., 2001). This bipolar structure of the MR complex is consistent with both the enzymatic role in DNA end processing and structural function in DNA end joining. Indeed the M2R2 heterotetramer contains two DNA binding/processing active sites, which could be important in the alignment of DNA ends in NHEJ or of DNA ends and sister chromatids in HR (Hopfner et al., 2002a). X-ray crystallographic data from the
The first domain contains the five phosphoesterase motifs which form the nuclease active site. This domain is composed of two parallel mixed β sheets that are flanked by seven α helices. The capping domain consists of a 5-stranded β sheet and two helices and partially caps the nuclease catalytic motifs of the N-terminal domain, suggesting that the capping domain might be involved in DNA-binding specificity (Hopfner et al., 2001). X-ray structure of
4.3. Physiological roles of Mre11-Rad50 complex
Genetic studies in eukaryotes indicate that the MR complex is required for genomic stability and is involved in a large variety of different functions in response to DSBs (Stracker and Petrini, 2011).
In archaea, the first evidence of the involvement of Mre11 in DNA repair process was demonstrated by Quaiser et al. (Quaiser et al., 2008), using an immunodetection approach to determine the roles of Mre11, Rad50, NurA and HerA proteins, in post-irradiation DNA repair in
Contrasting with the wealth of structural and biochemical data gained from the study of archaeal MR complex, the paucity and the conflicting nature of the genetic analyses underscore the importance to develop more effective genetic tools, for hyperthermophilic archaea in particular, to improve our knowledge on the functions of the complex in response to DSBs. Biochemical and
5. The Pab2263-NucS protein
5.1. Identification of a novel nuclease
Many nucleases are highly regulated by the sliding clamp PCNA (Proliferating Cell Nuclear Antigen). For instance, PCNA increases the affinity of Fen-1 for its substrate (Hutton et al., 2008) as well as catalytic rate of
Pab2263 belongs to the DUF91 family (Domain of Unknown Function 91) and, as many members of this family, contains the C-terminal domain that carries the characteristic residues forming the active site of the RecB family nucleases. This nuclease domain is found in many enzymes with potential functions in DNA replication and/or repair (Aravind et al., 2000). For instance, the DUF91 family members are found in euryarchaeota (59 homologues annotated in 2011), crenarchaeota (33 homologues), actinobacteria (259 homologues), and proteobacteria (41 homologues). Up to date, no eukaryotic member of the DUF91 family has been identified.
5.2. Structure of Pab2263-NucS
Crystallographic structure of Pab2263 has been solved (Ren et al., 2009; Ren et al., 2007) and is the first representative of the DUF91 family. Pab2263 is composed of two independent domains, separated by a long and flexible linker (~28Å). This multi-domain organisation is common for many nuclease domains which are often associated with helicase domains (Rouillon and White, 2010).
The C-terminal domain of this protein family displays the minimal endonuclease fold (Pingoud et al., 2005): an α/β structure composed of a five-stranded β-sheet and four flanking α helices. Active site is represented by a sequence motif conserved in the RecB-like nucleases (Aravind et al., 2000): E----[Gh]xxD----hxhh[ED]hK---QhxxY, where ‘h’ refers to hydrophobic residues (YFWLIVMA) and ‘---‘ indicates that the characteristic residues are not consecutive in the sequence. A conserved patch of four basic residues flanks one side of the cleft of the active site and might be involved in the binding of nucleic acids.
Strikingly, the N-terminal domain of Pab2263 displays a half-closed β-barrel, composed of height β-strands arranged in two antiparallel β-sheets. This fold was never previously described, but can remotely be seen as a structural homologue of the OB- or the Sm-folds, two folds that are involved in the binding of nucleic acid (Kambach et al., 1999; Theobald et al., 2003). In Pab2263, the potential binding site involves two patches of three consecutive basic residues, two conserved aromatic residues and a conserved arginine. High affinity ssDNA binding activity of the N-terminal domain was desmonstrated using site-directed mutagenesis and EMSA experiments (Ren et al., 2009).
The N-terminal domain displays a large hydrophobic patch exposed to the C-terminal domain, and is involved in the dimerisation of the protein. Dimer formation brings one extra residue of one monomer to the active site of the second monomer and the flexible linker cap the active site. As a result, the active site becomes a ‘closed’ channel, which indicates that the substrate for the enzyme must have a free end.
5.3. Activity of the Pab2263-NucS protein
Tests of various substrates on Pab2263 reveal its surprisingly broad range of substrate specificity. In agreement with the structural data indicating that the active site of the Pab2263 is located in the closed channel, this protein preferentially cleaves single stranded DNA, and was thus renamed ‘NucS’, for ‘NUClease specific for single-stranded DNA’. Under stoechiometric binding conditions, single-stranded regions of splayed arms, 3’ flaps and 5’ flaps are all cleaved by NucS, leaving only double-stranded products. Long single stranded DNA substrates are cleaved to regularly spaced products, which suggests that the protein could somehow measure its distance to the DNA end.
In high concentration of NucS, nuclease activity can invade to the double stranded DNA regions, suggesting that NucS proteins carry a weak helicase and/or unmelting activity of dsDNA. Important observation is that addition of PCNA directs the cleavage activity of
Pab2263-NucS is a founding member of a new family of structure-specific DNA endonuclease. The discovery of this novel nuclease family thus further indicates that archea contain many more nucleases than previously expected on the basis of search of homologous of ‘conventional’ eukaryotic or bacterial nucleases. For example, the Bax1 and GAN (GINS Associated Nuclease) nucleases from the DUF790 and Phosphoesterase RecJ-like families, respectively, have been identified in a similar manner (Li et al., 2011; Richards et al., 2008; Roth et al., 2009; Rouillon and White, 2010).
6. Conclusion
DNA repair pathways require the function of nucleases to ensure the removal of damages in DNA and thus integrity of the genetic information. The molecular mechanisms of the archaeal DNA nucleases reviewed in this work clearly underscore the conservation of the genetic information processing in archaea and eukarya. Whereas considerable amount of biochemical and structural data are available for archaeal DNA repair nucleases, their physiological roles remain less understood. More biochemical and genetic studies to investigate physiological functions of classical and recently discovered archaeal nucleases have clearly a strong potential to contribute to understanding complexity of eukaryotic DNA repair in the cellular context.
Acknowledgments
D.F., H.M, R.L., and C.R., were supported by grant ANR-07-BLAN-0371 from the National Research Agency. G.H., was supported by grant ANR-10-JC from the National Research Agency. H.M and R.L. also acknowledge support from the ANR Project RETYD(Y)DNA.
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