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Recq Helicase, in Concert with Reca and SSB Proteins, Initiates and Disrupts DNA Recombination

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Recq Helicase, in Concert with Reca and SSB Proteins, Initiates and Disrupts DNA Recombination Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press RecQ helicase, in concert with RecA and SSB proteins, initiates and disrupts DNA recombination Frank G. Harmon and Stephen C. Kowalczykowski1 Division of Biological Sciences, Sections of Microbiology and of Molecular and Cellular Biology, Graduate Group in Microbiology, University of California, Davis, California 95616 USA RecQ helicase is important to homologous recombination and DNA repair in Escherichia coli. We demonstrate that RecQ helicase, in conjunction with RecA and SSB proteins, can initiate recombination events in vitro. In addition, RecQ protein is capable of unwinding a wide variety of DNA substrates, including joint molecules formed by RecA protein. These data are consistent with RecQ helicase assuming two roles in the cell; it can be (1) an initiator of homologous recombination, or (2) a disrupter of joint molecules formed by aberrant recombination. These findings also shed light on the function of the eukaryotic homologs of RecQ helicase, the Sgs1, Blm, and Wrn helicases. [Key Words: Recombination; DNA repair; RecQ; RecA; helicase] Received January 6, 1998; revised version accepted February 20, 1998. Cells possess the capacity to repair DNA lesions brought recBC) mutations that allow recombination to proceed on by exposure to DNA-damaging agents (Friedberg et by an alternate pathway referred to as the RecF pathway al. 1995). Frequently, DNA repair is achieved by homo- (Kushner et al. 1971; Lloyd and Buckman 1985). The logous recombination, particularly when the damage RecF pathway defines a set of gene products that are results in a potentially lethal double-stranded DNA required for homologous recombination and recombina- (dsDNA) break. In general, repair mediated by homolo- tional repair in a recBCsbcBC background (for review, gous recombination requires that the dsDNA suffering see Clark and Low 1988; Mahajan 1988; Kowalczy- the lesion be separated into its component DNA strands. kowski et al. 1994). Recombination promoted by these The single-stranded DNA (ssDNA) formed by this pro- proteins is not confined solely to this specific genetic cessing step can then be used by homologous pairing background, but is also important for a number of recom- proteins such as the prokaryotic RecA protein and the bination processes in wild-type cells: Crossovers occur- eukaryotic Rad51 protein to promote homologous pair- ring at internal regions of duplex DNA, such as at ing and DNA strand invasion (Sung 1994; Maeshima et ssDNA gaps, are believed to be mediated by RecF path- al. 1995; Baumann et al. 1996; Gupta et al. 1997; for way gene products (Lanzov et al. 1991; Lloyd and Buck- review, see Kowalczykowski and Eggleston 1994; Cam- man 1995). In addition, these gene products play an im- erini-Otero and Hsieh 1995). portant role in repair of broken replication forks in wild- The processing step of recombination can be mediated type cells (Courcelle et al. 1997). Thus, rather than by a DNA helicase, a dsDNA nuclease, or a combination simply representing an alternate pathway, recombina- of these two activities. In wild-type Escherichia coli, tion directed by these proteins is a normal and important RecBCD enzyme is the helicase/nuclease responsible for means of genomic maintenance. initiating the majority of recombination events (for re- Nakayama et al. (1984) identified a component of this view, see Smith 1988; Kowalczykowski et al. 1994). Mu- repair pathway that is designated recQ. A null mutation tations at the recB or recC loci result in a 100- to1000- at this locus conferred both a significant reduction in re- fold decrease in recombination frequency, in addition to combination frequency (∼100-fold) and an increase in UV a dramatic increase in sensitivity to ionizing radiation sensitivity (∼20-fold) in a recBCsbcBC background (Na- (Howard-Flanders and Theriot 1966; Emmerson 1968). kayama et al. 1984, 1985). In addition, recQrecBCsbcBC However, both recombination proficiency and resistance cells are sensitive to the DNA damaging agents methyl- to ionizing radiation are restored to wild-type levels in a methane sulfonate (Mendonca et al. 1995) and hydrogen recBC background by extragenic sbcBC (suppressor of peroxide (Kusano et al. 1994). The RecQ protein is a 38 → 58 DNA helicase that acts 1Corresponding author. on both partially dsDNA and fully duplex DNA (Umezu E-MAIL [email protected]; FAX (916) 752-5939. et al. 1990). The ability to act at a flush dsDNA end is 1134 GENES & DEVELOPMENT 12:1134–1144 © 1998 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/98 $5.00; www.genesdev.org Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press RecQ helicase initiates and disrupts recombination shared among a small number of other helicases, includ- and disrupting nascent joint molecules. These findings ing the major initiator of homologous recombination, also provide insight into the potential roles of the the RecBCD enzyme (Taylor and Smith 1985). Recombi- eukaryotic homologs of RecQ helicase in DNA nation initiated by the RecBCD enzyme begins from metabolism. such a blunt dsDNA end present at a dsDNA break, pro- duced as the result of DNA damage, a broken replication fork, or conjugal DNA transfer. After binding to this end, Results the helicase and nuclease activities of RecBCD enzyme RecQ helicase initiates homologous pairing in vitro convert the dsDNA to a 38-ssDNA overhang, a product that is the preferred substrate for RecA protein-mediated A DNA helicase can act at either the initiation or DNA strand invasion (Konforti and Davis 1987; Anderson and heteroduplex extension phase of homologous recombi- Kowalczykowski 1997a,b; for review, see Kowalczy- nation. To address the possibility that RecQ helicase ini- kowski and Eggleston 1994). Because RecQ helicase also tiates homologous recombination, we tested its ability acts on blunt dsDNA ends and is needed for recombina- to produce a DNA substrate for RecA protein-promoted tion in a recBCsbcBC background, it was proposed to act joint molecule formation. In our assay system, used pre- as a functional analog of RecBCD enzyme during this viously to define an initiation function for the RecBCD processing step (Clark and Sandler 1994; Kowalczy- enzyme (Roman et al. 1991), RecA protein is provided kowski et al. 1994; Mendonca and Matson 1995). Thus, with a pair of homologous DNA substrates: Supercoiled the genetic data argue that, with the exception of a mi- DNA (scDNA) and 58–end labeled linear dsDNA (Fig. 1). nor contribution from both helicases II and IV, RecQ However, RecA protein is unable to pair these substrates protein is the only helicase of the 12 helicases in E. coli because neither contains ssDNA; thus, processing of the that can substitute for RecBCD enzyme function in ge- linear dsDNA to its component ssDNA strands is re- netic recombination. quired. If RecQ helicase can make ssDNA available to Recently, homologs of the RecQ helicase were identi- fied in a wide variety of organisms including the budding yeast Saccharomyces cerevisiae (Gangloff et al. 1994; Watt et al. 1995), the fission yeast Schizosaccharomyces pombe (Stewart et al. 1997), Caenorhabditis elegans, and Homo sapiens (Puranam and Blackshear 1994; Seki et al. 1994; Ellis et al. 1995; Yu et al. 1996). The yeast homo- log, Sgs1 protein, plays a key role in recombination, chromosome partitioning, and genome stability in S. cer- evisiae. Three proteins from human, encoded by the RECQL, BLM, and WRN genes, are also highly homolo- gous (∼40% identical among the helicase domains) to E. coli RecQ helicase and Sgs1 protein (Puranam and Black- shear 1994; Seki et al. 1994; Ellis et al. 1995; Yu et al. 1996). Mutations in the RECQL gene do not result in a discernible phenotype, but mutations at the BLM and WRN loci are linked to Bloom’s syndrome and Werner’s syndrome, respectively. Both of these disorders are rare, inherited diseases that share similar features including DNA replication abnormalities and pronounced geno- mic instability (Ellis et al. 1995; Yu et al. 1996). The phenotypic similarity of blm and wrn mutants and yeast sgs1 mutants suggests that all these helicases play simi- lar roles in DNA metabolism; the structural similarity of these three eukaryotic proteins and the prokaryotic RecQ helicase suggests that each may share a common Figure 1. RecQ helicase, in conjunction with RecA and SSB biochemical function. The potential for functional simi- proteins, initiates homologous pairing. Labeled, linear pUC19 larity among this group of proteins is further supported DNA and pUC1950 scDNA were incubated with: (Lane 1) RecA by the recent identification of the Sgs1, Wrn, and Blm and SSB proteins; (lane 2) RecQ helicase and SSB protein; (lanes proteins as 38 → 58 DNA helicases (Lu et al. 1996; Gray 3–8) all three proteins; (lane 9) RecQ helicase and RecA protein et al. 1997; Karow et al. 1997; Suzuki et al. 1997). alone. Slower migrating species that represent joint molecules, labeled Joint Molecules, are observed only in the presence of all For these reasons, in vitro analysis of purified RecQ three proteins. In a control reaction, RecA and SSB proteins helicase was carried out to determine whether this pro- were incubated with labeled linear pUC19 ssDNA, cold linear tein can mediate steps essential to homologous recom- pUC19 dsDNA, and pUC1950 scDNA to produce bona fide bination. The results presented here demonstrate that joint molecules (lane 10). All reactions were carried out as in the RecQ helicase is a multifunctional helicase that is Materials and Methods. Bands corresponding to linear ssDNA capable of both initiating homologous recombination and dsDNA are also indicated to the left. GENES & DEVELOPMENT 1135 Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Harmon and Kowalczykowski RecA protein, then homologous pairing products, joint molecules, will be observed by agarose gel electrophore- sis as species that migrate more slowly than either of the dsDNA substrates.
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