Rad51 Recombinase and Recombination Mediators

Through pairing and shuffling of related DNA sequences, homologous recombination (HR) 1The abbreviations used are: HR, homologous recombination; DSB, DNA double-stranded break; ssDNA, single-stranded DNA; dsDNA, double-stranded DNA; RPA, replication protein A. serves to create genetic diversity. In both mitotic and meiotic cells, HR is also an important mechanism for eliminating DNA double-stranded breaks (DSBs) (1Paques F. Haber J.E. Microbiol. Mol. Biol. Rev. 1999; 63: 349-404Crossref PubMed Google Scholar, 2Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (815) Google Scholar). Furthermore, HR is involved in restarting stalled DNA replication forks and provides a means for telomere length maintenance in cells lacking telomerase (3Cox M.M. Goodman M.F. Kreuzer K.N. Sherratt D.J. Sandler S.J. Marians K.J. Nature. 2000; 404: 37-41Crossref PubMed Scopus (871) Google Scholar, 4West S.C. Nat. Rev. Mol. Cell Biol. 2003; 4: 435-445Crossref PubMed Scopus (809) Google Scholar, 5Oakley T.J. Hickson I.D. DNA Repair (Amst.). 2002; 1: 175-207Crossref PubMed Scopus (45) Google Scholar, 6Michel B. Flores M.J. Viguera E. Grompone G. Seigneur M. Bidnenko V. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8181-8188Crossref PubMed Scopus (250) Google Scholar). Accordingly, defects in HR result in sensitivity to genotoxic agents, mitotic and meiotic chromosome aberrations, and destabilization of the genome (7Kolodner R.D. Nature. 2000; 407: 687-689Crossref PubMed Scopus (14) Google Scholar, 8Richardson C. Jasin M. Cold Spring Harbor Symp. Quant. Biol. 2000; 65: 553-560Crossref PubMed Scopus (13) Google Scholar). Recent evidence points to a role of HR in cancer prevention via the tumor suppressors BRCA1 and BRCA2 (9Pierce A.J. Stark J.M. Araujo F.D. Moynahan M.E. Berwick M. Jasin M. Trends Cell Biol. 2001; 11: S52-S59Abstract Full Text PDF PubMed Scopus (235) Google Scholar). At the core of all HR reactions lies the ability of the recombination machinery to utilize a ssDNA molecule, derived from the processing of DSBs or stalled DNA replication forks (1Paques F. Haber J.E. Microbiol. Mol. Biol. Rev. 1999; 63: 349-404Crossref PubMed Google Scholar, 2Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (815) Google Scholar, 3Cox M.M. Goodman M.F. Kreuzer K.N. Sherratt D.J. Sandler S.J. Marians K.J. Nature. 2000; 404: 37-41Crossref PubMed Scopus (871) Google Scholar, 5Oakley T.J. Hickson I.D. DNA Repair (Amst.). 2002; 1: 175-207Crossref PubMed Scopus (45) Google Scholar, 6Michel B. Flores M.J. Viguera E. Grompone G. Seigneur M. Bidnenko V. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8181-8188Crossref PubMed Scopus (250) Google Scholar, 10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar), to invade a homologous duplex. The product of this DNA strand invasion reaction is a structure called D-loop, and the overall enzymological process is referred to as homologous DNA pairing and strand exchange (Fig. 1) (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar). Resolution of the D-loop is accomplished by one of a number of pathways (1Paques F. Haber J.E. Microbiol. Mol. Biol. Rev. 1999; 63: 349-404Crossref PubMed Google Scholar, 2Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (815) Google Scholar) to yield recombinants that either entail a reciprocal exchange of genetic information flanking the initiation site (crossover recombinants) or not (non-crossover recombinants). The homologous DNA pairing and strand exchange reaction is mediated by a class of conserved recombinase enzymes: UvsX in bacteriophage T4, RecA in Escherichia coli, and Rad51 in eukaryotes (11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar, 12Bleuit J.S. Xu H. Ma Y. Wang T. Liu J. Morrical S.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8298-8305Crossref PubMed Scopus (68) Google Scholar). Studies conducted in the past several years have helped define a set of operational principles for the Rad51 recombinase and have unveiled an array of ancillary factors of Rad51. Genetic analyses of DNA double-stranded break repair and mitotic and meiotic recombination in the budding yeast Saccharomyces cerevisiae have led to the identification of genes collectively known as the RAD52 epistasis group (1Paques F. Haber J.E. Microbiol. Mol. Biol. Rev. 1999; 63: 349-404Crossref PubMed Google Scholar, 2Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (815) Google Scholar). Among the members of the RAD52 group, RAD51 is, arguably, the most famed. The RAD51-encoded product has structural homology to E. coli RecA and T4 UvsX proteins and is highly conserved among eukaryotes (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar, 13Story R.M. Bishop D.K. Kleckner N. Steitz T.A. Science. 1993; 259: 1892-1896Crossref PubMed Scopus (145) Google Scholar). In many respects, Rad51 behaves like RecA in homologous DNA pairing and strand exchange. The recombinase activity of Rad51 can be described in three kinetic phases. The Presynaptic Phase—Like RecA, Rad51 forms a right-handed helical filament on ssDNA in which the DNA is held in an extended state (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar, 14Yu X. Jacobs S.A. West S.C. Ogawa T. Egelman E.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8419-8424Crossref PubMed Scopus (205) Google Scholar). The Rad51-ssDNA nucleoprotein filament, often referred to as the presynaptic filament, contains a binding site for dsDNA. The initiating ssDNA substrate is bound within the “primary” site of the presynaptic filament, and the homologous duplex resides within the “secondary” site (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar). The capability to hold two DNA molecules in close proximity underlies the ability of the presynaptic filament to form DNA joints between these molecules. Interestingly, even though Rad51 hydrolyzes ATP (15Sung P. Science. 1994; 265: 1241-1243Crossref PubMed Scopus (754) Google Scholar), presynaptic filament assembly requires only ATP binding (2Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (815) Google Scholar, 10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar, 16Sung P. Stratton S.A. J. Biol. Chem. 1996; 271: 27983-27986Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Rad51 nucleates onto ssDNA rather slowly, thus rendering presynaptic filament assembly vulnerable to competing factors. In fact, replication protein A (RPA), a classical ssDNA-binding protein, while playing an important role in Rad51-mediated recombination, also paradoxically competes with Rad51 for binding sites on the initiating ssDNA substrate. A number of accessory proteins, termed recombination mediators (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 12Bleuit J.S. Xu H. Ma Y. Wang T. Liu J. Morrical S.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8298-8305Crossref PubMed Scopus (68) Google Scholar) (see below), promote the nucleation of Rad51 onto ssDNA and in doing so help Rad51 overcome the inhibitory effect of RPA (Fig. 2) (2Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (815) Google Scholar, 10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 12Bleuit J.S. Xu H. Ma Y. Wang T. Liu J. Morrical S.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8298-8305Crossref PubMed Scopus (68) Google Scholar). The Synaptic Phase—Herein, the incoming duplex is incorporated into the presynaptic filament through multiple contact points and then sampled for homology. Extensive studies with RecA have yielded no evidence for progressive scanning of the duplex in homology search. Rather, to test for homology, the incoming duplex is held transiently within the secondary binding site of the RecA presynaptic filament, and if homology is not found, the duplex is released. This cycle of binding and release of the duplex goes on until homology is located. Given its structural and functional similarities to RecA, it seems reasonable to assume that the Rad51 presynaptic filament also employs the same random collision mode of homology search (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar). However, Rad54 may endow the presynaptic filament with the ability to scan the incoming duplex molecule for homology (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 17Ristic D. Wyman C. Paulusma C. Kanaar R. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8454-8460Crossref PubMed Scopus (110) Google Scholar, 18Van Komen S. G. S. Stratton S. Sung P. Mol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) (see a DNA and homology is the of the duplex and its with the ssDNA molecule through DNA joints that in The which from a DNA The of is by the of DNA strand (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar, E. S. M. Mol. 1999; 4: Full Text Full Text PDF PubMed Scopus Google Scholar). the the of the the the for it to form joints with its ssDNA E. S. M. Mol. 1999; 4: Full Text Full Text PDF PubMed Scopus Google Scholar). However, which transiently DNA (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 18Van Komen S. G. S. Stratton S. Sung P. Mol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), promote with DNA that have a the the two molecules into homologous it is (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar, E. S. M. Mol. 1999; 4: Full Text Full Text PDF PubMed Scopus Google Scholar). The is a DNA is which in the is to be in the initiating ssDNA substrate (Fig. The two DNA in the bound by and (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar). The Phase—Herein, the strand in the duplex molecule is into the presynaptic filament to with the initiating the result is the of the DNA This process is referred to as strand or The of DNA is by the length of the presynaptic A effect of Rad54 on the reaction has Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google Scholar) (see its ability to and help secondary structure in ssDNA, RPA a role in DNA pathways that entail the of a ssDNA The of RPA in recombination is has both and on the recombination The effect of RPA is most DNA used (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar), only a effect of RPA is as L. Van Komen S. Y. J. H. T. Sung P. Nature. 2003; PubMed Scopus Google Scholar). RPA Rad51 presynaptic filament assembly by secondary structure in ssDNA molecules (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, 11Bianco P.R. Tracy R.B. Kowalczykowski S.C. Front Biosci. 1998; 3: 570-603Crossref PubMed Google Scholar). In by ssDNA, RPA the DNA joints to a reaction R.B. M.M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). RPA also ssDNA from the of duplex DNA into the secondary binding site of the Rad51 presynaptic filament Komen S. G. S. Sung P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of the of RPA for ssDNA, an of RPA is either with or to Rad51 to the ssDNA, assembly of the presynaptic filament is (2Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (815) Google Scholar, 10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, P. 11: PubMed Scopus Google Scholar, T. Kowalczykowski S.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This of RPA has used as the for recombination mediators (Fig. 2) (2Symington L.S. Microbiol. Mol. Biol. 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The presynaptic of Rad54 is with the that the of Rad51 to is in meiotic S. cerevisiae cells lacking Rad54 M. Bishop D.K. A. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). in cells for the of DNA Rad51 is J. E. J. Kanaar R. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). a in Rad51 to a has by in the S. cerevisiae B. Komen S. Sung P. Mol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Rad54 Rad51 and ssDNA (10Krejci L. Chen L. Van Komen S. Sung P. Tomkinson A. Prog. Nucleic Acids Res. Mol. Biol. 2003; 74: 159-201Crossref PubMed Scopus (58) Google Scholar, B. Komen S. Sung P. Mol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), Rad54 Rad51 onto ssDNA to presynaptic filament a with Rad51 through its and via several of a conserved called the S.C. Nat. Rev. Mol. Cell Biol. 2003; 4: 435-445Crossref PubMed Scopus (809) Google Scholar, L. T. S. M. Nature. 2002; PubMed Scopus Google Scholar, S.C. Nat. 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