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PERSPECTIVE
1 Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA; 2 Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA
DNA replication is tightly regulated in a cell cycle to ensure the integrity of genomic information during successive passages. The replication process can be divided into three major steps as follows: the initial assembly of prereplication complex (pre-RC) at the replication origin, the distortion of the origin (or origin melting) for replication initiation, and the elongation phase during DNA synthesis. In this process, long stretches of double-stranded DNA (dsDNA) must be unzipped in a relatively short time window within a cell growth cycle. The daunting task of unzipping is carried out by a class of efficient molecular machines called helicases, which are shown to be ring-shaped oligomers. Here, we will focus on the current understanding of the replicative helicases involved in cellular and viral DNA replication in eukaryotic cells.
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General features of helicases for DNA replication |
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 Top General features of helicases... Replicative helicase: a double...Regulation of helicase activity...The helicase action after...Double hexamer vs. bidirectional...Concluding remarksAcknowledgmentsReferences |
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), which is essential for converting the chemical energy of ATP to the mechanical forces for unwinding duplex DNA.
The helicase proteins from various replication systems have different structural and biochemical states, most of which are not active as the helicase for replication. One example is the relatively well-characterized viral replicative helicases in eukaryotic cells, such as SV40 large T antigen (LTag) or papillomavirus early gene product 1 (E1), which are mostly monomeric or dimeric in the inactive state (Dean et al. 1992; Sedman et al. 1997; Sanders and Stenlund 2000; Gai et al. 2004a). However, to become active for DNA replication, these helicase proteins need to be assembled and loaded onto origin DNA as ring-shaped oligomers that encircle the dsDNA (Wessel et al. 1992; Fouts et al. 1999; Valle et al. 2000).
Another example is the eukaryotic minichromosome maintenance (MCM) protein complex that contains six paralogs numbered MCM2–MCM7 (Tye 1999; Lei and Tye 2001). The six MCM proteins can be in a trimer, dimer, and monomer conformation when they are not functioning as the helicase for DNA replication (Ishimi 1997; Schwacha and Bell 2001; Davey et al. 2003). Early work in Schizosaccharomyces pombe fission yeast showed that purified MCM2–MCM7 complexes formed a ring-shaped structure consistent with a hexamer unit of stoichiometry (meaning a 1:1 ratio of six proteins to form a hexamer; Adachi et al. 1997; Lee and Hurwitz 2000). Many Archaeal species represent simpler replicative helicase systems, as they have only one MCM gene that is homologous to the eukaryotic genes. However, the single MCM protein can form homo-oligomers (Kelman et al. 1999), and evidence suggests that hexamers and double hexamers are likely to be the active helicase form (Chong et al. 2000; Fletcher et al. 2003). Interestingly, EM studies of the Methanobacterium thermoautotrophicum MCM (mtMCM) showed a haptameric ring structure (Yu et al. 2002), albeit hexameric structure is observed (Pape et al. 2003). The haptameric form is also observed for T7 helicase (Toth et al. 2003). The presence of the seven-subunit ring at least suggests some plasticity in assembly, although its physiological relevance awaits further studies.
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Replicative helicase: a double-headed molecular machine |
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; Valle et al. 2000; Gomez-Lorenzo et al. 2003), that is, the two hexamers contact each other through the N-terminal domains in the middle of the double hexamer, with the helicase ring locating on the two ends and pointing away from each other (Fletcher et al. 2003; Gomez-Lorenzo et al. 2003). If the helicase rings on both ends of the double hexamer are active in unwinding DNA simultaneously, the helicase is a bona-fide double-headed molecular machine.
The double hexamer as the functional form was first suggested for LTag through biochemical, genetics and EM studies (Mastrangelo et al. 1989; Simmons 2000). LTag is in a monomeric state that equilibrates with a hexameric form in solution (Dean et al. 1992; Li et al. 2003; Gai et al. 2004a). Monomeric LTag, which contains an origin-binding domain (OBD) that recognizes the replication origin of SV40, can bind the origin sequence and assemble into a double hexamer in the presence of ATP. This assembly does not involve any accessory proteins factors (such as a loader). The double-hexamer assembly triggers origin distortion/melting and becomes active in unwinding the duplex DNA when ATP and Mg++ are available (Borowiec et al. 1991). Obviously, the conversion of the inactive monomeric LTag into the active double-hexameric helicase at the origin provides an opportunity for regulating the helicase activity spatially and structurally. It is worth noting that LTag single hexamers also posses helicase activity (Smelkova and Borowiec 1997; Alexandrov et al. 2002; Uhlmann-Schiffler et al. 2002; Gai et al. 2004a). However, double hexamers have about 15 times higher helicase activity than single hexamers. More importantly, LTag mutants defective in hexamer–hexamer interactions fail to replicate DNA (Weisshart et al. 1999; Barbaro et al. 2000), indicating the requirement for the double-hexamer architecture, albeit the basis for such a requirement is unclear yet.
The crystal structure of the N-terminal half of mtMCM confirms the double-hexamer architecture for the first time at the molecular level. It also extends the case for the double-hexameric architecture to eukaryotic cells (Fletcher et al. 2003). The mtMCM structure reveals the detailed molecular interactions for the double-hexamer formation, which is also in a head–head configuration, like that seen for LTag. Using the mtMCM structure as a guide, multiple-sequence alignment showed convincingly that the structures of the poorly conserved N-terminal half of MCM proteins from various organisms are conserved, strongly suggesting that MCM in different eukaryotic cells may also function as a double hexamer for DNA replication.
Another relatively well-characterized helicase for DNA replication in eukaryotes is the papillomavirus E1, about which extensive biochemical and structural data have been obtained. Papillomavirus and polyomavirus (including SV40) are closely related, and the similarity between them ranges from the virus particle structures (both with T = 7 icosahedron symmetry) to the genomic organization. Even the sequence of the helicases from the two viruses are homologous, both containing an N-terminal OBD that recognizes and binds replication origin, and a C-terminal helicase domain that has an activity of nonsequence-specific DNA binding. Not surprisingly, like SV40 LTag, papillomavirus helicase protein E1 was observed to form the bilobed structure as revealed by EM studies, suggestive of a double-hexamer architecture as well (Fouts et al. 1999; Lin et al. 2002). Similar to LTag, the assembly of the double hexamer at the origin is regulated by ATP (Sanders and Stenlund 1998). However, one unique feature for E1 helicase assembly is the participation of another factor, a viral protein called E2 (discussed in detail below).
In prokaryotic cells, no direct physical evidence exists for a double-hexameric helicase in DNA replication. The DnaB helicase has been observed to be hexameric on the basis of studies using biochemical and EM approaches. However, because replication in prokaryotes is also bidirectional, and there is no strong evidence to the contrary, a double-hexamer architecture for DnaB helicase during replication could not be ruled out at this time (Kornberg and Baker 1992).
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Regulation of helicase activity though assembly and activation |
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TopGeneral features of helicases...Replicative helicase: a double...Regulation of helicase activity...The helicase action after...Double hexamer vs. bidirectional...Concluding remarksAcknowledgmentsReferences |
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; Prasanth et al. 2004; Fig. 1A). The recruited MCM complex at the origin is initially inactive and becomes activated through the actions of CDK and DDK kinases. For SV40 virus that replicates in eukaryotic host cells, LTag utilizes its OBD to specifically target the helicase to the viral replication origin for the assembly of an active double-hexameric helicase (Fig. 1B; Arthur et al. 1988; Borowiec et al. 1990). Thus, LTag bypasses the cellular regulatory factors such as Cdt1/CDC6 and kinases for recruitment, loading, and activation, allowing it to self-assemble into an active helicase, a mechanism necessary for the efficient replication of viral DNA.
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) in the previous issue of Genes & Development. The authors report the X-ray structure of a complex containing the papillomavirus E1 and E2 proteins (Fig. 1C). The crystal structure of E1–E2 complex contains the ATPase domain of E1 helicase and the activation domain of E2. E2 protein is a transcription factor that contains an activation domain at the N terminus and a DNA-binding/dimerization domain at the C terminus. The DNA-binding domains of both E1 and E2 recognize particular sequences at the replication origin, and the binding sites for E1 and E2 are juxtaposed to allow the simultaneous binding of the two full-length E1 and E2 complex with much increased specificity for the origin (Mohr et al. 1990; Sedman and Stenlund 1995; Chen and Stenlund 2000). In the full-length version of E1 and E2, two copies of E1–E2 (E12–E22) may form a stable heterotetramer for targeting the origin in a highly specific manner (Chen and Stenlund 1998). In the crystal structure of the complex, E1–E2 forms a 1:1 heterodimer complex, which reflects the E1–E2 interactions in the full-length E12–E22 heteroteramer complex.
The structure of the E1–E2 complex of Abbate et al. (2004) reveals three important features that provide significant insights into how papillomavirus regulates its helicase assembly at the replication origin. The first feature is that the ATPase domain of E1 can be modeled into a hexamer that is very similar to that of LTag helicase domain. The similarity of the structures between E1 and LTag permits the modeling of the E1 monomer into the LTag hexamer structure by superpositioning the E1 ATPase domain with that of the LTag. The modeled E1 hexamer also shows the very similar 
-hairpin structure seen in LTag hexameric central channel (Gai et al. 2004b). Evidence suggests that these -hairpins may be important for DNA-binding and helicase activity, possibly for translocating and unwinding the dsDNA (Abbate et al. 2004; Gai et al. 2004b; Reese et al. 2004). A similar -hairpin structure is also present in the central channel of mtMCM N-terminal double hexamer (Fletcher et al. 2003), despite the gross difference in the overall folding of MCM and the viral helicases.
The second feature revolves around the E1–E2 interaction. According to the E1 hexamer model, E2 binds to E1 near the hexamerization interface, and thus should prevent E1 hexamer formation (Fig. 1D). On the basis of the E1–E2 structure, as well as on previous structural and biochemical data, Abbatte et al. (2004) proposed a molecular mechanism of how E2 regulates the assembly of E1 into the hexameric helicase. At first look, this regulation appears to be purely inhibitory. E2 prevents E1 from forming a hexamer by binding to the oligomerization interface. However, through its specific DNA-binding activity at the origin, E2 enhances E1's specific DNA binding to the origin (Sedman et al. 1997; Stenlund 2003), thus playing a shuttling role, or matchmaker role, for targeting E1 to the origin of replication for latter events of the conversion to an active helicase, a process still not well understood. Considering the role of E2 in helicase assembly at the origin, E2 can also be regarded as an E1 helicase loader, the equivalent of which does not exist for SV40 LTag.
This regulation of E1 helicase by the association with E2 may also be important for preventing the intrinsic nonsequence-specific DNA binding by E1 helicase at nonorigin locations (Stenlund 2003; Abbate et al. 2004). The matchmaker role may be particularly critical in helping E1 to find the origin of viral DNA, because both E1 and viral DNA are at very low abundance at the beginning of the viral infection. The E1–E2 complex binds to the origin with greatly increased affinity and specificity, possibly achieved through cooperative binding of E1 and E2 at the origin (Mohr et al. 1990; Sanders and Stenlund 1998). Once bound to the origin, E2 finishes its matchmaker task, and continued association with E1 will inhibit the assembly of E1 into an active helicase. The results of Abbate et al. (2004) reveal a third important feature that shows the interplay between E2–E1 binding/dissociation and E1 assembly. The dissociation of E2 from the origin has been postulated to be an ATP-dependent process (Sanders and Stenlund 1998), but the E1–E2 complex structure by Abatte et al. (2004) has provided the structural basis for a molecular mechanism for an ATP-dependent E2 dissociation and E1 assembly. Here, ATP binding serves as an allosteric effector to change the conformation of E1 and disengage E2 (Fig. 1D; see also Figs. 6, 7 in Abbate et al. 2004), permitting the ATP-dependent hexamerization/double hexamerization of E1 into the active helicase form for replication.
Regulation of replication through the recruitment of a helicase to the origin is actually first described in the classical case of a prokaryotic virus system, the coliphage 
. Coliphage does not have its own replicative helicase, and sequesters the host hexameric helicase DnaB for its genomic replication (Mallory et al. 1990). Similar to the papillomavirus system, a virus protein P binds the DnaB to form a complex and then targets it to the viral origin of replication. However, the helicase activity of DnaB recruited is inhibited in the P–DnaB-O complex at the origin, even though the helicase is already in a hexameric form (Alfano and McMacken 1989a). In this case, however, the helicase is activated by removing the inhibitory P from the complex, an action carried out by host heat-shock proteins, leading to the initiation of DNA replication (Alfano and McMacken 1989b). The phage wins the competition for recruiting DnaB to the viral origin (instead of the host origin) through the higher affinity of P to DnaB, as well as the high affinity of the P–DnaB complex to the viral origin. In this regard, the recruitment of MCM helicase to the origin by Cdc6 and Cdt1 in the formation of eukaryotic pre-RC complex also is similar (Stillman 1994). However, in eukaryotes, the activation of the MCM helicase is modulated through another level of regulation by the actions of CDK and DDK protein kinases, which may be important for linking the DNA replication to the cell cycles through cyclin-dependent kinases (Waga and Stillman 1998; Forsburg 2004).
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The helicase action after assembly and activation |
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TopGeneral features of helicases...Replicative helicase: a double...Regulation of helicase activity...The helicase action after...Double hexamer vs. bidirectional...Concluding remarksAcknowledgmentsReferences |
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). This method has later been applied to detect the origin melting in other replicative helicase systems, such as papillomavirus E1 (Sanders and Stenlund 1998) and yeast MCM (Geraghty et al. 2000).
The crystal structures of LTag helicase domain have provided structural insights into a possible molecular mechanism of how LTag helicase can untwist/distort and melt the origin through an iris-like motion (Li et al. 2003). The structures obtained from different crystallization conditions, as well as in different nucleotide-binding states (Gai et al. 2004b), reveal an iris-like motion of the hexameric rings of LTag helicase. In this iris-like motion, the two tiers of the hexameric helicase untwist/twist relative to each other slightly (permitted by the gap between the two tiers and the long-spring like 
-helix connecting the two tiers), and the central hexameric channel expands/constricts like an iris of the eye responding to the change of light. This iris-like motion likely generates distortion and melting of the duplex dsDNA bound to the central channel.
The predicted regions to be distorted and melted in the iris model are the regions bound by the helicase domain of the double hexamer. These regions correspond to the AT-rich and EP region of SV40 origin, which agrees well with the earlier biochemical results (Borowiec et al. 1991). In this mechanism, the central OBD domain is proposed to function only for origin binding, and not for origin melting, a conclusion supported by prior studies (Chen et al. 1997; Li et al. 2003). In this respect, the functions of the helicase domain for origin melting and replication fork unwinding are separated from that of the OBD that specializes in targeting LTag to the origin.
In the case of papillomavirus E1, unlike LTag, origin untwisting and melting may be directly linked to the OBD of E1 (Enemark et al. 2000, 2002). Binding of a single OBD dimer of E1 to the origin is reported to cause local distortion at the origin (Sanders and Stenlund 1998). This distortion becomes even more pronounced when the dimer is converted to tetramers, and the further assembly of E1-OBD into the hexamer/double hexamer likely causes the ultimate melting at the origin.
For eukaryotic cells, it is not yet clear what role the MCM helicase plays in the melting of the origin. The ORC complex, the equivalent of DnaA from Escherichia coli, is also thought to play a role in origin melting. In E. coli, DnaA protein distorts and melts the origin DNA (oriC) to reveal small ssDNA regions before the DnaB helicase unwinds the DNA (Kornberg and Baker 1992). However, recent evidence in eukaryotic system suggests that, like the case in SV40 LTag, MCM may perform the actual melting of the origin. In yeast, permanganate sensitivity at the ARS1 origin is only detected after DDK action in S phase (Geraghty et al. 2000). The mcm5-bob1 mutation, which presumably produces a constitutively active MCM helicase without DDK action (Sclafani et al. 2002), produces the permanganate sensitivity even in G1 phase, when the DNA is not being replicated. The phosphorylation may allow the MCM2–MCM7 complex to undergo a conformational change that can distort and melt the origin DNA.
It is also not clear as to how the MCM helicase performs origin melting and fork unwinding upon activation. Nonetheless, two different mechanisms are proposed. The first is that the multiple MCM complexes located at a distance from both sides of the origin act as rotary motors to melt the origin and unwind the replication forks (Laskey and Madine 2003). The second is that MCM proteins are located at the origin and function in a similar way as proposed for LTag (Li et al. 2003). Additional mechanisms likely exist. Regardless, the recent evidence of MCM possessing origin-melting function provides a unifying theme for the dual roles of origin melting and replication fork unwinding by all eukaryotic replicative helicases.
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Double hexamer vs. bidirectional replication fork unwinding |
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The recent crystal structures of Ltag, as well as mtMCM, in combination with other biochemical and structural evidence (Borowiec et al. 1990; Wessel et al. 1992; Smelkova and Borowiec 1998), prompted us to propose a looping-model topology to resolve the paradox of a double-hexamer helicase and two propogating replication forks (Li et al. 2003). Two key observations in the LTag structure provide support for this looping model. One is the presence of a positively charged side-channel on the wall of LTag hexamer (Fig. 2A,B), and the second is the large, highly positively charged chamber seen inside the helicase. The side-channels are present in mtMCM (Fig. 2C; Fletcher et al. 2003; Pape et al. 2003) and likely to be present in the hexamers of papillomavirus E1 and other replicative helicases. In the proposed looping model, ssDNA loops out from the side channel in two possible topologies (Fig. 2D,E; Li et al. 2003; Gai et al. 2004b), whereas the dsDNA is pulled into the helicase domain of the double hexamer by the action of the ATP-binding and hydrolysis (Gai et al. 2004b). In the LTag helicase domain, the interior chamber is sufficiently wide for separating dsDNA into ssDNA and can provide exit for the unwound ssDNA through the side channel located the widest point of the interior chamber.
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Concluding remarks |
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TopGeneral features of helicases...Replicative helicase: a double...Regulation of helicase activity...The helicase action after...Double hexamer vs. bidirectional...Concluding remarksAcknowledgmentsReferences |
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; Fletcher et al. 2003; Li et al. 2003; Abbate et al. 2004). The double-hexamer architecture may be the consequence of constraint for a common function required for a replicative helicase, that is, origin melting and bidirectional fork unwinding. The different sequences and structural folds may reflect the difference in the regulation of helicases and interactions with other replication proteins in their respective systems. The currently available information obtained by the combination of X-ray crystallography, NMR, and biochemical/genetic approaches has greatly facilitated our understanding of the helicase functions during DNA replication. The high-resolution structures determined for different helicases from various systems also provide a basis for more detailed functional studies through site-directed mutagenesis. So far, the high-resolution structures of helicase domain and OBD have been determined for LTag, mtMCM, and papilloma virus E1 as separate entities. In the future, one challenge is to understand how the different parts and domains are organized in an intact molecule, which should allow a better understanding of the helicase function for origin melting and replication fork unwinding in different systems. Because the replicative helicases for DNA replication in higher eukaryotes belong to the AAA+ protein family that constitutes a group of hexameric molecular machines functioning in various cellular processes (helicase, protein unfolding, membrane fusion, etc.), the studies of these helicases should also contribute to the understanding of the mechanisms of other AAA+ hexameric molecular machines.
Although our focus is on the discussion of helicase function and its regulation, we should bear in mind that many other protein components also actively participate in the process of DNA replication. In fact, the double hexamer of LTag and MCM helicases serve as assembly platforms for other replication proteins (e.g., RPA, polymerases, etc.) to form larger functional complexes, such as primosome or replisome (Simmons 2000; Forsburg 2004). Understanding the assembly, regulation, and functions of these larger complexes in DNA replication present exciting challenges in the future, which likely require the collaborative work of scientists from many different fields.
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Acknowledgments |
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Footnotes |
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3 Corresponding author. E-MAIL Xiaojiang.Chen{at}uchsc.edu or Xiaojiang.Chen{at}usc.edu; FAX (303) 315-8113. 
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68 Å wide) is wide enough for strand separation. Blue areas are positively charged surfaces, red represents negatively charged surface. (B) A cut-away view of the surface representation of the electron density for the X-ray structure of LTag helicase domain filtered to 20 Å resolution, showing the same side channel as in A. (C) A cut-away view of the surface representation of the EM reconstruction of a mtMCM hexamer (Pape et al. 2003