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Home , Helicase, Methanopyrus, Replisome, Topoisomerase, Topoisomerase IV, Type II topoisomerase

Journal of Science 110, 1345-1350 (1997) 1345 Printed in Great Britain © The Company of Biologists Limited 1997 JCS9577

COMMENTARY When and meet!

Michel Duguet Laboratoire d’Enzymologie des Acides Nucléiques, Institut de Génétique et Microbiologie, URA 2225 CNRS, Université Paris-Sud, 91405 Orsay Cedex, France (e-mail: [email protected])

SUMMARY

Several examples of direct interactions between finding of an interaction between type II topoisomerase and and have recently been described. The data the helicase in yeast. This interaction possibly allows suggest a possible cooperation between these in the faithful segregation of newly replicated in major DNA events such as the progression of a replication eukaryotic cells. A fourth example is the interaction between fork, segregation of newly replicated chromosomes, disrup- the same helicase Sgs1 and topoisomerase III in yeast, that tion of nucleosomal structure, DNA supercoiling, and finally may control recombination level and genetic stability of recombination, repair, and genomic stability. A first example repetitive sequences. Recently, in humans, in is the finding of a strong interaction between T and similar to Sgs1 have been found to be responsible for topoisomerase I in mammalian cells, that may trigger Bloom’s and Werner’s syndromes. The cooperation between unwinding of the parental DNA strands at the replication helicases and topoisomerases is likely to be extended to many forks of Simian Virus 40. A second example is the reverse aspects of DNA mechanisms including condensa- gyrase from thermophilic , composed of a tion/decondensation. putative helicase domain, and a topoisomerase domain in the same polypeptide. This may be required to maintain Key words: Replication fork, segregation, genomic stability at high temperature. A third example is the Nucleosome, DNA supercoiling, Recombination, Genetic stability

INTRODUCTION Several recent examples of interactions of helicases with topoisomerases suggest a cooperation between these two Early in evolution, the choice was made to have the plectone- classes of enzymes in many aspects of DNA mechanisms (Fig. mic DNA double helix as the carrier of genetic information. 1). These include progression of the DNA replication fork, seg- From this initial choice, it was necessary to solve the topo- regation of newly replicated chromosomes, disruption of logical problem of separating the two DNA strands in order nucleosomal structure (especially during ), DNA to allow the proper transmission of the genetic information. supercoiling, and finally DNA recombination, repair, and Two steps are required for this process: (1) disruption of stability. hydrogen bonds between the two strands, performed by spe- cialized enzymes called DNA helicases (reviewed by Lohman, 1993); and (2) elimination of all the topological links between PROGRESSION OF THE REPLICATION FORK the two strands, performed by DNA topoisomerases (reviewed by Wang, 1996). These considerations led to the suggestion In the late seventies, it was suggested that the topological that DNA helicases and topoisomerases are both required to problems arising at a replication fork could in principle be solved provide the swivel mechanism for DNA replication, postulated by two different mechanisms (Champoux and Been, 1980; more than three decades ago by Cairns (1963). Forterre et al., 1980). The first consists of the removal of the Surprisingly, various models for the , a compact positive supercoils arising in front of the replication fork, as the replication complex comprising DNA / and parental strands rotate. In eukaryotic cells, this may be achieved helicases, did not generally integrate a topoisomerase indifferently by topoisomerase I or II (Kim and Wang, 1989; (Kornberg, 1978). The first indication of a cooperation between DiNardo et al., 1984), although the former enzyme appears the a helicase and a topoisomerase came from studies on phage more efficient because of its highly processive relaxing activity ΦX174 DNA replication. An interaction between the host (Roca, 1995). In prokaryotic cells, DNA gyrase (topoisomerase encoded rep DNA helicase and the phage A II), efficiently removes positive supercoils, and may function product (a sequence specific topoisomerase) allows for strand ahead of the fork (Wu et al., 1988), while topoisomerase I separation of the phage DNA replicative form (Scott and (protein ω) is probably less involved, as it is unable to bind pos- Kornberg, 1978; Duguet et al., 1978). itively supercoiled DNA (Kirkegaard and Wang, 1985). Fig. 2A 1346 M. Duguet depicts a hypothetical swivelase (see also Fig. 5) formed by the would explain why a defect in a helicase that does not interact association of a helicase and a topoisomerase. In this model, the with topoisomerase II does not result in chromosome unstability two enzymes are part of a large replication complex anchored in (i.e. XPD or ERCC2). a fixed structure (i.e. the nuclear matrix) and the replicating DNA Very recently, two human genes, BLM and WRN (respec- is translocated through the protein complex (Kornberg, 1988). tively 43% and 38% identical to Rec Q, and 44% and 34% to The helicase actively separates the two parental DNA strands SGS-1 over the 400 sequence of the helicase while the topoisomerase, working in front of the helicase, allows region) have been identified as responsible for Bloom’s and relaxation of positive supercoils in a highly processive manner. Werner’s syndromes (Ellis et al., 1995; Yu et al., 1996). Similar Indeed, a direct interaction between eukaryotic topoisomerase I to mutations in SGS-1, mutations in BLM and WRN result in and T antigen was recently described, that may trigger DNA chromosomal breakage, translocations, intra and interchromo- unwinding at the SV40 replication forks (Simmons et al., 1996). somal strand exchange. Furthermore, a reduction in 1 M NaCl The second mechanism to prevent positive supercoiling at the extractible topoisomerase II was found in Bloom’s cells treated replication fork allows newly replicated DNA duplexes to by BrdU (Heartlein et al., 1987). untangle (Champoux and Been, 1980; Forterre et al., 1980), Finally, it is noteworthy that SGS-1 (and perhaps the human instead of rotating the parental duplex. This may be achieved by genes) not only interact in vivo with topoisomerase II, but also a type II topoisomerase working behind the helicase and able to in a distinct pathway with topoisomerase III, an interaction that perform transient double strand breaks in the DNA. Such a is presumably required to reduce the level of recombination mechanism is likely to occur at the end of replication (see below). (see section on recombination and genome stability).

SEGREGATION OF NEWLY REPLICATED DISRUPTION OF NUCLEOSOMAL STRUCTURE CHROMOSOMES Replication and transcription require that the DNA be accessible It has been proposed long ago that proper chromosome segre- to the enzymatic machineries involved in these processes. It was gation presents a major topological problem, both in eukaryotic suggested, at least for the initiation steps, that nucleosomal struc- and in prokaryotic cells, because of the intertwining of newly tures must be transiently disrupted, then reassembled on newly replicated DNA molecules (Sundin and Varshavsky, 1980). replicated DNA or after passage of a transcription complex Failure to solve this problem results in breakage of chromo- (Bonne-Andrea et al., 1990; Adams and Workman, 1993). somes, non-disjunction, and eventually cell death (Holm et al., Nucleosome disruption may occur via the positive super- 1989; Uemura et al., 1987; Spell and Holm, 1994). The essential coiling produced by a helicase tracking through the DNA role of type II topoisomerases (Topo II in , gyrase or duplex in the presence of a topoisomerase. This idea is based Topo IV in ) in the untangling of chromosomes has been on the twin supercoiled model imagined by Liu and Wang well recognized (DiNardo et al., 1984; Adams et al., 1992). (1987) for transcription. In the hypothetical model in Fig. 2C, Fig. 2B shows schematically the problem arising when two the helicase locally separates the DNA strands in front of the forks meet at the end of replication (Champoux and Been, 1980; topoisomerase, producing positive supercoils ahead and Forterre et al., 1980; Wang, 1991; Holm, 1994). As pointed out negative supercoils behind (Liu and Wang, 1987; Koo et al., by Holm, when the tracking DNA helicases approach each other, 1991). Positive supercoiling is absorbed by nucleosome dis- any double helical turn in the parental duplex is converted into ruption, while negative supercoiling is removed by the topoi- one intertwining between the two daughter molecules. Topoiso- somerase, allowing the double helix to rewind. This implies merase II removes these intertwinings by its double-strand that the topoisomerase acting in this process may selectively breaking/passing/rejoining activity (Wang, 1996). Thus, a remove negative supercoils (like prokaryotic topo I), or that helicase working at a replication fork and a type II topoisomerase positive supercoils are not targeted for immediate removal. working in association with it, may cooperate to perform chro- Nucleosome disruption was recently demonstrated by mosome segregation. Until recently, this cooperation remained a Ramsperger and Stahl (1995), who showed that purified SV40 T matter of hypothesis. Studies in yeast, however, may have antigen, acting as a helicase on SV40 replication origin, was able changed this perspective. Indeed, in a search for inter- to displace nucleosomes . The reaction was only observed acting in vivo with the C-terminal domain of topoisomerase II in on a DNA with free ends, suggesting that the negative super- yeast, Watt and coworkers (1995) used the two-hybrid cloning coiling produced behind the helicase must be removed, while strategy (Fields and Song, 1989). They found an interacting positive supercoiling might be absorbed by nucleosome disrup- protein named SGS-1, a putative helicase whose was tion in front of the helicase*. The authors proposed that in vivo, previously described as a top3 suppressor (Wallis et al., 1989, see a modified topoisomerase may remove the negative supercoiling. section on recombination). SGS-1 shows strong sequence simi- As mentioned above, direct binding of T antigen to topoiso- larity to RecQ helicase (Umezu et al., 1990). merase I was recently demonstrated (Simmons et al., 1996). Deletion of SGS-1 results in increased chromosomal mis-segre- The model of nucleosome removal does not, of course, only gation and high levels of non-disjunction at I. The authors apply to replication, but also to repair, transcription, and also showed that SGS-1 and Topo II likely act in the same chro- recombination. Indeed, helicases appear systematically associ- mosome segregation pathway. This latter finding indicates that ated with repair and transcription complexes (Buratowski, in yeast is probably promoted by a 1993; Seroz et al., 1995) and might be used in concert with a direct cooperation between topoisomerase II and a helicase, possibly SGS-1. If the interpretation is correct, any defect in the *Addition of topo I or II (both able to relax positive or negative supercoils with the same efficiency) in the reaction with circular DNA did not permit nucleosome disruption, pre- functioning of this segregation machine (helicase or topoiso- sumably because both topoisomerases also remove the positive stress necessary for dis- merase II mutations) would result in chromosome breakage. This ruption. When helicase and topoisomerase meet 1347

Progression of a Segregation of newly A Replication Fork ? replicated Chromosomes ?

AAAAAA T AAAAAAAA AAAAAA AAAAAAAA AAAAAA AAAAAAAA H matrix Helicase Replication + complex Topoisomerase

Recombination B and genome Disruption of stability? nucleosomal structure and Topo II Helicase transcription ? DNA supercoiling ?

Fig. 1. Putative cooperation of helicases with topoisomerases in DNA metabolism. topoisomerase to disrupt chromatin structure in an appropriate region. The same model may work in reverse to promote nu- C cleosome assembly, if a topoisomerase removing positive supercoils works in front of the helicase: then, negative super- coils generated behind the helicase may serve to assemble nucleosomes, instead of being relaxed by a topoisomerase. T H Such a machine may serve as a negative supercoiling force in eukaryotes and may explain why there is no bacterial-like DNA gyrase activity in these (see Fig. 3C). normal helix Overwinding Very recently, Hamiche and Prunell proposed that positive (positive supercoiling) supercoiling may trigger the flipping of the (H3-H4)2 tetramer from a left-handed to a right-handed form (Hamiche et al., 1996). They suggested that the positive supercoiling produced T H in front of a transcription complex may be absorbed by this histone flipping; this mechanism then behaves as a ‘eukaryotic gyrase’, leaving negative supercoils behind the complex.

DNA SUPERCOILING: THE CASE OF REVERSE Fig. 2. Interaction between helicases and topoisomerases in DNA GYRASE FROM replication and nucleosome disruption. (A) The swivel machine is represented by the association of a 3′ topoisomerase I (green) with a Reverse gyrase, discovered in hyperthermophilic archaebacte- helicase (red) anchored on a fixed structure, i.e. the nuclear matrix. 3′ ria (Kikuchi and Asai, 1984), has the unique property of being Topo I is the usually found in eukaryotes that able to increase the DNA linking number, producing positive binds the 3′ end of the broken DNA strand, and removes positive or supercoils in a relaxed circular DNA at the expense of ATP negative supercoils with the same efficiency. As replicating DNA (reviewed by Duguet, 1995). moves through the structure, the two parental strands (black) are separated by the helicase, while positive supercoiling is removed by the Mechanistic studies have shown that reverse gyrase tran- 3′ topoisomerase. (B) A machine able to separate the daughter siently cleaves a single DNA strand, forming a covalent link molecules at the end of replication is formed by a helicase (red) with the 5′ end, a characteristic of eubacterial topoisomerase I removing the last turns of parental DNA and a type II topoisomerase (Jaxel et al., 1989). How does an ATP-dependent topoiso- (green) untangling the daughter duplexes. (C) Nucleosome disruption. merase I promote a reaction of supercoiling? A strong clue is The positive supercoiling produced by the translocating helicase H (red) given by sequence data, showing that reverse gyrase is made destabilizes the nucleosome, while a topoisomerase T (5′ or 3′ Topo I, of both a helicase-like domain and a topoisomerase I domain or eukaryotic topo II, green) efficiently relaxes the negative in the same polypeptide (Confalonieri et al., 1993). supercoiling, reforming the normal duplex behind the helicase. 5′ Topo I is the type I topoisomerase, usually found in prokaryotes, and also Fig. 3A,B describes a plausible mechanism of positive DNA ′ supercoiling derived from the model of Liu and Wang (1987): present in yeast. It binds the 5 end of the broken DNA strand and exclusively removes negative supercoils. Note that in this figure (and in tracking of the helicase domain through the DNA duplex Figs 3 and 5), helicases and topoisomerases are represented by rings would produce two waves of supercoiling, positive in front, around the DNA double-helix. Several recent data on the spatial and negative behind. Specific relaxation of the negatively structure of these enzymes suggest that they indeed form ring supercoiled region by the associated topoisomerase domain structures. would produce net positive supercoils. It is noteworthy that the early models of negative supercoiling by bacterial DNA gyrase Other examples of supercoiling by a helicase-plus-topoiso- were based on this principle with specific relaxation of positive merase mechanism have been described where helicase and supercoils (Gellert et al., 1978) (Fig. 3C). topoisomerase are not associated in the same polypeptide (Koo 1348 M. Duguet

H merase domains. Such functions may also have been conserved A in eukaryotic cells (see below). As first suggested by Kikuchi (1990), reverse gyrase may be used as a powerful ‘renaturase’ or ‘reformatase’ (see Fig. 5) to eliminate a variety of abnormal DNA structures such as extruded DNA cruciforms, triple DNA Underwinding Overwinding (negative supercoiling) (positive supercoiling) helices, Z DNA, mismatch regions, or even recombination inter- mediates. Alternatively, reverse gyrase may help to rapidly B 5'T H rewind the double helix after passage of a transcription complex or during the of recombination junctions. All these processes must be especially destabilizing at high temper- ature as the two DNA strands are less tightly associated.

Normal Helix Overwinding (positive supercoiling) RECOMBINATION AND GENOME STABILITY Reverse gyrase C The essential role that DNA helicases play in genetic recombi- H 3'T nation and genome stability has long been recognized. In contrast, the role that topoisomerases play in these processes still remains obscure. It was proposed by Wang et al. (1990) that this role is a ‘double-edged sword’: on the one hand, topoisomerases Underwinding Normal Helix (negative supercoiling) may be necessary to promote recombination by their strand-trans- ferase activity and (or) by allowing formation of plectonemically "Gyrase-like activity" wound recombination intermediates. On the other hand, topoiso- Fig. 3. DNA supercoiling by the cooperation of a helicase and a merases may help to repress recombination, via mechanisms that topoisomerase. (A) The translocating helicase (red) produces negative are not presently understood (Wang et al., 1990). supercoiling upstream and positive supercoiling downstream. (B) If a Possible clues to the role of topoisomerases in recombination 5′ topo I (green) works behind the helicase to specifically relax and genome stability recently emerged through their interactions negative supercoils, the machine continously increases the DNA with helicases. The first clue is provided by a recent report that linking number and is a reverse gyrase. (C) If a 3′ topo I (green) works a helicase is able to transform a frozen intermediate of topoiso- in front of the helicase to remove positive supercoils, then the machine merase II bound to DNA into a permanent double-strand break decreases the DNA linking number and behaves as a ‘gyrase’. in vitro (Howard et al., 1994). This is illustrated in Fig. 4A, where tracking helicases displace the non-covalently bound 3′ ends, et al., 1991; Zhang et al., 1990; Quinn et al., 1996). Indeed, generating a double-strand break upon dissociation of topoiso- recently, a reverse gyrase with two different subunits has been merase II subunits. This mechanism may be used in vivo to isolated from a hyperthermophilic (Kozyavkin et provide the DNA breaks necessary to initiate recombination al., 1994; Krah et al., 1995). (Szostak et al., 1983). Indeed, recent analysis of the DS breaks Finally, the ubiquitous presence of a reverse gyrase activity in occurring in yeast meiosis indicate that the 5′ DNA ends are cova- all of the hyperthermophilic organisms so far tested, archaebac- lently bound to Spo 11 (Keeney et al., 1997), a member of an terial or eubacterial (Bouthier de la Tour et al., 1991), addresses atypical topoisomerase II family recently discovered in the the question of its biological function. The simplest idea is that (Bergerat et al., 1997). Since the archaebacterial enzyme, positive supercoiling prevents DNA from melting at high tem- called Topo VI, presents a classical topoisomerase II activity, an perature (Kikuchi and Asai, 1984). However, we can speculate attractive hypothesis is that in yeast, Spo 11, modified by its inter- on other more subtle roles for reverse gyrase, which take action with a helicase, is responsible for this cleavage activity. advantage of a cooperation between the helicase and topoiso- A second series of observations may explain the dual role of A TOPO II B Cleavage Site 1 Site 2

T H T H Heteroduplex binding to site 2 Helicase binding to site 1

Fig. 4. Putative cooperation between helicases and Disruption of recombination branch migration topoisomerases in . intermediate (A) Production of a permanent double-strand Strand displacement break from a topo II cleavable complex by strand displacement involving a helicase (see Szostak et al., 1983). (B) The putative role of helicase/topoisomerase complexes in the Dissociation suppression of recombination intermediates or, on the contrary, in the promotion of branch migration. When helicase and topoisomerase meet 1349

H 3'T migration. Thus, by removing ‘undesired’ heteroduplex Swivelase regions as well as various abnormal DNA structures, helicase/topoisomerase complexes may contribute to genome stability and (or) promote recombinational exchange.

CONCLUDING REMARKS Although most of the ideas presented here remain speculative, TII H one can imagine that cooperation between helicases and topoi- Segregatase somerases has been exploited again and again in living cells.

Daughter Moreover, as suggested in Fig. 5, the various combinations of DNA duplexes helicases and topoisomerases may produce different kinds of Parental strands machines working on DNA. For instance, with a 3′ topoisomerase I placed in front of a helicase, the machine may work as a ‘swivelase’ acting in DNA replication, or acting in front of a transcription complex. In the absence of replication, the machine could also work as a 5'T H Reformatase ‘gyrase’, producing net negative supercoiling, or as a chromatin assembly machine (see also Fig. 3). AAAAAAA AAAAAAA With a type II topoisomerase behind the helicase, the machine may work as a ‘segregatase’, to separate newly repli- Abnormal DNA Normal Helix Structure cated daughter chromosomes at the end of replication. Finally, with a 5′ topoisomerase behind a helicase, the Fig. 5. Possible DNA machines by various combinations of machine may work as a ‘reformatase’, disrupting chromatin helicase/topoisomerase complexes. Note that: (i) the ‘swivelase’ may structure and eliminating all kinds of altered DNA structures, work independently of replication, either in front of a transcription including cruciforms, Z DNA regions, triple helices, mismatch complex, or as a chromatin assembly machine; (ii) the ‘reformatase’ or slippage regions in repetitive sequences, or immature recom- may also work to rewind the duplex behind the transcription complex. bination intermediates. It may also work as a ‘reverse gyrase’, producing net positive supercoiling into DNA. topoisomerases as activators or repressors of recombination. It would be interesting to test these different possibilities, in Several years ago, a new type I topoisomerase, named Topo III particular the disruption of chromatin structure or the elimina- was discovered in yeast through the hyper-recombination and tion of recombination intermediates at least in vitro. slow growth phenotype of its mutants (Wallis et al., 1989). In any case, one can confidently predict that in the future, Remarkably, this eukaryotic topoisomerase belongs in fact to greater evidence for the cooperation between helicases and the prokaryotic topoisomerase I family, since it binds the 5′ ends topoisomerases in the maintenance and stability of the genome of DNA and specifically removes negative supercoils (Kim and will appear. Wang, 1992). A unique suppressor of top3 null mutations was isolated and turned out to be the putative helicase SGS-1, or I thank my laboratory colleagues for fruitful discussions, and David slow growth suppressor (Gangloff et al., 1994) also named TPS- E. Adams for critical reading of the manuscript. The Laboratoire d’Enzymologie des Acides Nucléiques is supported by funds from 1, for topoisomerase supressor (Romeo et al., 1992). 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