Bloom DNA Helicase Facilitates Homologous Recombination between Diverged Homologous Sequences

Abstract

Bloom syndrome caused by inactivation of the Bloom DNA helicase (Blm) is characterized by increases in the level of sister chromatid exchange, homologous recombination (HR) associated with cross-over. It is therefore believed that Blm works as an anti-recombinase. Meanwhile, in Drosophila, DmBlm is required specifically to promote the synthesis-dependent strand anneal (SDSA), a type of HR not associating with cross-over. However, conservation of Blm function in SDSA through higher eukaryotes has been a matter of debate. Here, we demonstrate the function of Blm in SDSA type HR in chicken DT40 B lymphocyte line, where Ig gene conversion diversifies the immunoglobulin V gene through intragenic HR between diverged homologous segments. This reaction is initiated by the activation-induced cytidine deaminase enzyme-mediated uracil formation at the V gene, which in turn converts into abasic site, presumably leading to a single strand gap. Ig gene conversion frequency was drastically reduced in BLM−/− cells. In addition, BLM−/− cells used limited donor segments harboring higher identity compared with other segments in Ig gene conversion event, suggesting that Blm can promote HR between diverged sequences. To further understand the role of Blm in HR between diverged homologous sequences, we measured the frequency of gene targeting induced by an I-SceI-endonuclease-mediated double-strand break. BLM−/− cells showed a severer defect in the gene targeting frequency as the number of heterologous sequences increased at the double-strand break site. Conversely, the overexpression of Blm, even an ATPase-defective mutant, strongly stimulated gene targeting. In summary, Blm promotes HR between diverged sequences through a novel ATPase-independent mechanism. Bloom syndrome caused by inactivation of the Bloom DNA helicase (Blm) is characterized by increases in the level of sister chromatid exchange, homologous recombination (HR) associated with cross-over. It is therefore believed that Blm works as an anti-recombinase. Meanwhile, in Drosophila, DmBlm is required specifically to promote the synthesis-dependent strand anneal (SDSA), a type of HR not associating with cross-over. However, conservation of Blm function in SDSA through higher eukaryotes has been a matter of debate. Here, we demonstrate the function of Blm in SDSA type HR in chicken DT40 B lymphocyte line, where Ig gene conversion diversifies the immunoglobulin V gene through intragenic HR between diverged homologous segments. This reaction is initiated by the activation-induced cytidine deaminase enzyme-mediated uracil formation at the V gene, which in turn converts into abasic site, presumably leading to a single strand gap. Ig gene conversion frequency was drastically reduced in BLM−/− cells. In addition, BLM−/− cells used limited donor segments harboring higher identity compared with other segments in Ig gene conversion event, suggesting that Blm can promote HR between diverged sequences. To further understand the role of Blm in HR between diverged homologous sequences, we measured the frequency of gene targeting induced by an I-SceI-endonuclease-mediated double-strand break. BLM−/− cells showed a severer defect in the gene targeting frequency as the number of heterologous sequences increased at the double-strand break site. Conversely, the overexpression of Blm, even an ATPase-defective mutant, strongly stimulated gene targeting. In summary, Blm promotes HR between diverged sequences through a novel ATPase-independent mechanism. The RecQ helicases, a subfamily of DNA helicases, carry out the unwinding of duplex DNA in the 3′ to 5′ direction. Homologs of RecQ have been identified in a wide range of organisms, from budding yeast to humans (reviewed in Ref. 1Cobb J.A. Bjergbaek L. Nucleic Acids Res. 2006; 34: 4106-4114Crossref PubMed Scopus (51) Google Scholar). There are five human RecQ family proteins: Blm, Wrn, RecQ1, RecQ4, and RecQ5. The BLM, WRN, and RECQ4 genes are mutated in Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome, respectively (1Cobb J.A. Bjergbaek L. Nucleic Acids Res. 2006; 34: 4106-4114Crossref PubMed Scopus (51) Google Scholar, 2Hickson I.D. Nat. Rev. Cancer. 2003; 3: 169-178Crossref PubMed Scopus (582) Google Scholar, 3Kitao S. Shimamoto A. Goto M. Miller R.W. Smithson W.A. Lindor N.M. Furuichi Y. Nat. Genet. 1999; 22: 82-84Crossref PubMed Scopus (585) Google Scholar). A hallmark of Bloom syndrome cells is the drastic increase in the level of sister chromatid exchange (SCE), 4The abbreviations used are: SCEsister chromatid exchangeHRhomologous recombinationDSBdouble-strand breakSDSAsynthesis-dependent strand annealHJHolliday junctionTSAtricostatin AsIgMsurface IgMIRionizing radiation. which results from homologous recombination (HR) associated with cross-over of the DNA damage caused during DNA replication (4Chaganti R.S. Schonberg S. German J. Proc. Natl. Acad. Sci. U.S.A. 1974; 71: 4508-4512Crossref PubMed Scopus (793) Google Scholar, 5Sonoda E. Sasaki M.S. Morrison C. Yamaguchi-Iwai Y. Takata M. Takeda S. Mol. Cell. Biol. 1999; 19: 5166-5169Crossref PubMed Scopus (373) Google Scholar). It is therefore believed that Blm acts as an anti-recombination factor and inhibits aberrant recombination. This idea is supported by the observation that Sgs1, the yeast ortholog of Blm, facilitates the resolution of aberrant joint molecules during meiotic HR (6Jessop L. Lichten M. Mol. Cell. 2008; 31: 313-323Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 7Oh S.D. Lao J.P. Taylor A.F. Smith G.R. Hunter N. Mol. Cell. 2008; 31: 324-336Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) and following replication blockage (8Branzei D. Sollier J. Liberi G. Zhao X. Maeda D. Seki M. Enomoto T. Ohta K. Foiani M. Cell. 2006; 127: 509-522Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). sister chromatid exchange homologous recombination double-strand break synthesis-dependent strand anneal Holliday junction tricostatin A surface IgM ionizing radiation. HR plays a critical role in the maintenance of genome stability by repairing DNA double-strand breaks (DSBs) and releasing replication blockages at damaged template strands (9San Filippo J. Sung P. Klein H. Annu. Rev. Biochem. 2008; 77: 229-257Crossref PubMed Scopus (1215) Google Scholar, 10Branzei D. Vanoli F. Foiani M. Nature. 2008; 456: 915-920Crossref PubMed Scopus (221) Google Scholar). The current model for HR-mediated DSB repair is that DSBs are processed to produce a 3′ single-stranded overhang, along which Rad51 is polymerized (11Pâques F. Haber J.E. Microbiol. Mol. Biol. Rev. 1999; 63: 349-404Crossref PubMed Google Scholar, 12Symington L.S. Microbiol. Mol. Biol. Rev. 2002; 66: 630-670Crossref PubMed Scopus (832) Google Scholar). The resulting Rad51-DNA filament undergoes homology search and strand invasion into intact homologous duplex DNA, leading to the formation of the D-loop structure. DNA synthesis from the invading strand followed by dissociation from the homologous duplex DNA and subsequent re-annealing of the newly synthesized strand with the other end of the DSB completes the repair. This type of HR, referred to as synthesis-dependent strand anneal (SDSA), results in sequence transfer from the intact template sequence (donor) to the damaged DNA (recipient), and accounts for the majority of mitotic HR (11Pâques F. Haber J.E. Microbiol. Mol. Biol. Rev. 1999; 63: 349-404Crossref PubMed Google Scholar, 13Johnson R.D. Jasin M. EMBO J. 2000; 19: 3398-3407Crossref PubMed Scopus (471) Google Scholar). Extensive strand exchange of the D-loop, on the other hand, leads to the generation of Holliday junction (HJ) intermediates. SDSA does not cause cross-overs, whereas HR involving the Holliday junction often causes cross-overs, such as SCE and meiotic HR. An increase in the level of SCE in Bloom syndrome cells therefore supports the idea that Blm suppresses the formation of HJ as well as recombinogenic DNA lesions. This idea is supported by the biochemical evidence of the Blm-dependent resolution of Holliday junctions (14Wu L. Hickson I.D. Nature. 2003; 426: 870-874Crossref PubMed Scopus (885) Google Scholar). On the other hand, in Drosophila, DmBlm is known to facilitate the repair of DSB by promoting SDSA (15Adams M.D. McVey M. Sekelsky J.J. Science. 2003; 299: 265-267Crossref PubMed Scopus (208) Google Scholar, 16McVey M. Larocque J.R. Adams M.D. Sekelsky J.J. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 15694-15699Crossref PubMed Scopus (76) Google Scholar). However, the role of Blm in SDSA in the other higher eukaryotic cells has not been defined. BLM−/− cells established from the chicken DT40 B lymphocyte line exhibit a marked increase in the frequency of both SCE and targeted integration (17Kohzaki M. Hatanaka A. Sonoda E. Yamazoe M. Kikuchi K. Vu Trung N. Szüts D. Sale J.E. Shinagawa H. Watanabe M. Takeda S. Mol. Cell. Biol. 2007; 27: 2812-2820Crossref PubMed Scopus (39) Google Scholar, 18Imamura O. Fujita K. Itoh C. Takeda S. Furuichi Y. Matsumoto T. Oncogene. 2002; 21: 954-963Crossref PubMed Scopus (86) Google Scholar, 19Otsuki M. Seki M. Inoue E. Yoshimura A. Kato G. Yamanouchi S. Kawabe Y. Tada S. Shinohara A. Komura J. Ono T. Takeda S. Ishii Y. Enomoto T. J. Cell Biol. 2007; 179: 53-63Crossref PubMed Scopus (18) Google Scholar), as do human Bloom syndrome cells (20So S. Nomura Y. Adachi N. Kobayashi Y. Hori T. Kurihara Y. Koyama H. Genes Cells. 2006; 11: 363-371Crossref PubMed Scopus (22) Google Scholar, 21So S. Adachi N. Lieber M.R. Koyama H. J. Biol. Chem. 2004; 279: 55433-55442Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). In this study, the chicken DT40 we the role of Blm in SDSA induced by DNA To this we this type of SDSA to Ig gene conversion and gene targeting. Ig gene conversion diversifies the Ig gene through HR during in This reaction is initiated by activation-induced cytidine uracil formation at the M. K. S. S. Y. T. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. Sale J.E. M.S. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Science. 2002; PubMed Scopus Google Scholar). is to an abasic site, leading to a M. Sonoda E. K. Sale J.E. K. Kikuchi K. Y. K. Y. Takeda S. Genet. PubMed Scopus Google Scholar). This in the the sequence transfer of a single to from an of from the to the V EMBO J. PubMed Scopus Google Scholar, T. K. Sonoda E. K. Kikuchi K. C. F. K. N. Takeda S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. Sale J.E. Kikuchi K. H. K. Takeda S. Sonoda E. Mol. Cell. Biol. 2008; PubMed Scopus Google Scholar) donor and segments have an sequence Ig gene conversion are to Ig V segments. Ig gene conversion is by SDSA the formation of a Holliday of Ig gene conversion a to the role of Blm in activation-induced cytidine sequence of Ig gene conversion can the of HR. Ig gene gene targeting is by The of DSBs by a at the increases the frequency of gene targeting by of and the frequency of gene targeting can by the of a gene P. F. Jasin M. Mol. Cell. Biol. PubMed Scopus Google Scholar) that the of Blm drastically the of Ig gene conversion the of the gene conversion that Blm plays a role in the of This is an Blm is in believed to HR recombination between diverged homologous sequences. To understand the function of Blm in we the of heterologous sequences a DSB on DSB repair. The demonstrate that Blm can promote SDSA is sequence between the damaged DNA and the homologous donor Blm has both and on HR, the type of DNA damage and the of the HR targeting with in into the The cells in with and chicken at of DNA for and as M. Sasaki M.S. Sonoda E. Morrison C. M. H. Yamaguchi-Iwai Y. Shinohara A. Takeda S. EMBO J. PubMed Scopus Google Scholar). was used for BLM−/− cells established from a of DT40 cells that is for EMBO J. PubMed Scopus Google Scholar). that BLM−/− cells the as type cells by the Ig The of Ig gene conversion was by the of as T. K. Sonoda E. K. Kikuchi K. C. F. K. N. Takeda S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). by of cells that been for and with IgM To Ig gene tricostatin A was to a of In the of cells was as the of cells is at higher the of cells. DNA was from at of segments into a and to sequence was by with DNA of for for and for with and as J.E. Takata M. Takeda S. M.S. Nature. PubMed Scopus Google Scholar). into the and with the an the of from the sequences in between and gene conversion was out as J.E. Takata M. Takeda S. M.S. Nature. PubMed Scopus Google Scholar). cells in of and of targeting DNA with and human and was used as a The targeting DNA was by from the to DNA at for for and for with the and the number of cells was and the cells to with of The cells for and the HR by the following HR frequency number of of cells in the of number of cells by measured as A. S. Sonoda E. M. Takeda S. Y. M. Takata M. EMBO J. PubMed Scopus Google Scholar). To the role of Blm in we the of Ig gene To this we measured the of surface IgM in from type and BLM−/− cells that have a in the as M. Sonoda E. K. Sale J.E. K. Kikuchi K. Y. K. Y. Takeda S. Genet. PubMed Scopus Google Scholar, EMBO J. PubMed Scopus Google Scholar, T. K. Sonoda E. K. Kikuchi K. C. F. K. N. Takeda S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the is by gene conversion from segments to Ig the level of the frequency of gene conversion from of type and BLM−/− of of BLM−/− cells showed a in whereas of type cells showed a in the in the BLM−/− cells was to the of we the type and BLM−/− in the of a which increases the frequency of Ig gene conversion in DT40 cells H. M. H. Takeda S. T. Ohta K. Nat. PubMed Scopus Google Scholar), to gene conversion the of of in the of of the type cells whereas of BLM−/− cells to of in that the of was for type cells and for BLM−/− cells results that Blm the of Ig gene Blm increase the of gene conversion and to the of Ig V To the of Ig gene we the sequences of Ig segments. cells for in the of the Ig segments from the cells by and the sequences of the the type gene conversion in of Ig sequences gene conversion in of Ig sequences in the BLM−/− cells gene conversion not in the BLM−/− that the of HR is not by the of results that Blm increase the of Ig gene conversion in DT40 cells. To the role of Blm in Ig gene we the of the gene conversion and the of on the gene conversion that caused the cells from BLM−/− that been to for and the sequences of segments from type cells used a of segments as a donor However, BLM−/− cells used limited of the of the gene conversion used the and used the The sequences of and segments have a higher identity with the compared with segments that used in type cells. Blm promote gene conversion with diverged donor to the of Ig V To the marked in the frequency of Ig gene conversion in BLM−/− cells is caused by in HR, we Blm is required for HR between sequences. this we measured HR repair by the number of breaks in cells following ionizing in the DSBs are by HR the intact sister chromatid by end in DT40 cells M. Sasaki M.S. Sonoda E. Morrison C. M. H. Yamaguchi-Iwai Y. Shinohara A. Takeda S. EMBO J. PubMed Scopus Google Scholar). cells in the not in the can the we can HR between sister by breaks in mitotic cells at E. T. Zhao S. K. M. T. Takata M. Takeda S. EMBO J. 2003; 22: PubMed Scopus Google Scholar). BLM−/− cells showed increased of breaks as (17Kohzaki M. Hatanaka A. Sonoda E. Yamazoe M. Kikuchi K. Vu Trung N. Szüts D. Sale J.E. Shinagawa H. Watanabe M. Takeda S. Mol. Cell. Biol. 2007; 27: 2812-2820Crossref PubMed Scopus (39) Google Scholar, 18Imamura O. Fujita K. Itoh C. Takeda S. Furuichi Y. Matsumoto T. Oncogene. 2002; 21: 954-963Crossref PubMed Scopus (86) Google Scholar, 19Otsuki M. Seki M. Inoue E. Yoshimura A. Kato G. Yamanouchi S. Kawabe Y. Tada S. Shinohara A. Komura J. Ono T. Takeda S. Ishii Y. Enomoto T. J. Cell Biol. 2007; 179: 53-63Crossref PubMed Scopus (18) Google Scholar). measured the number of breaks at of the number of breaks from this number to the number of breaks The number of breaks increased in BLM−/− compared with type cells This observation is in marked with the increase in the number of breaks in cells M. Sasaki M.S. Sonoda E. Morrison C. M. H. Yamaguchi-Iwai Y. Shinohara A. Takeda S. EMBO J. PubMed Scopus Google Scholar). Blm plays a in HR the intact sister the critical role by Blm in Ig gene conversion into this of sister DSB repair in BLM−/− cells that Blm is for HR between diverged sequences not for HR between sequences. Blm promotes HR between diverged homologous sequences. To this we a gene targeting the of gene targeting a of targeting DNA to K. Y. Hatanaka A. Sonoda E. H. Adachi N. Y. Koyama H. Jasin M. Takeda S. Mol. Cell. Biol. PubMed Scopus Google Scholar). BLM−/− cells the at the of the a at This the targeted integration of donor DNA into and the in sequence in leading to the of the the of gene targeting donor has the homology to the whereas has the the to in are and heterologous sequences the of with and The of donor into results in the of sequences from the sequences of the that the does not the of the gene not as K. Y. Hatanaka A. Sonoda E. H. Adachi N. Y. Koyama H. Jasin M. Takeda S. Mol. Cell. Biol. PubMed Scopus Google Scholar). targeting donor with the into the BLM−/− measured the frequency of gene targeting by the number of targeting in the BLM−/− cells for the the cells by the of a gene targeting in BLM−/− cells for the donor the cells. the of the gene targeting frequency in BLM−/− cells to that in the cells and that the BLM−/− cells showed a of gene targeting in the of of heterologous sequences in the compared with the cells. with the for Ig gene conversion strongly that Blm facilitates HR between diverged homologous sequences. To Blm facilitates HR between diverged homologous sequences, we the role of Blm in homologous in HR. To this we the of gene targeting a of type of homologous to There are heterologous sequences the of with of targeting in in the cells by frequency of the gene targeting increased as the of homologous increases However, gene targeting in BLM−/− cells not increased even a homologous that limited the of the homologous is used in BLM−/− cells results that Blm facilitates homologous in HR, are heterologous sequences the DSB site. a biochemical that the of DNA is by the reaction of Blm and a 5′ to 3′ double-strand DNA (reviewed in Ref. N. L.S. DNA 2004; 3: PubMed Scopus Google Scholar), HR J. P. Proc. Natl. Acad. Sci. U.S.A. 2008; PubMed Scopus Google Scholar). To the between Blm and in HR between diverged sequences, we Blm and in type cells harboring the at the and measured gene targeting as a donor There are heterologous sequences of with the frequency of gene targeting was drastically increased by the overexpression of Blm On the other hand, gene targeting was increased a by the of Blm and compared with the overexpression of Blm results the idea that overexpression of Blm can promote HR, presumably at the such as 3′ formation at the subsequent formation of the D-loop structure. to this can an HR a the of Blm has a on HR, in with the overexpression of To the Blm-dependent of HR, we of Blm is required for HR between diverged sequences. To this we a human Blm in type cells harboring the and measured gene targeting as the donor type human Blm increased the gene targeting to the as chicken Blm of the Blm the gene targeting as as the type Blm This observation is in with the biochemical that the Blm as well as type Blm strand exchange between single-stranded DNA and homologous duplex DNA J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In summary, Blm promote HR between diverged sequences through an mechanism. It has been that Blm acts as an and the generation of HJ recombination A. Hickson I.D. Proc. Natl. Acad. Sci. U.S.A. 2000; PubMed Scopus Google Scholar) as well as aberrant recombination following replication blockage (9San Filippo J. Sung P. Klein H. Annu. Rev. Biochem. 2008; 77: 229-257Crossref PubMed Scopus (1215) Google Scholar, 10Branzei D. Vanoli F. Foiani M. Nature. 2008; 456: 915-920Crossref PubMed Scopus (221) Google Scholar). The that both SCE and gene targeting are in the of Blm is with the idea that Blm plays a role in the of HR (20So S. Nomura Y. Adachi N. Kobayashi Y. Hori T. Kurihara Y. Koyama H. Genes Cells. 2006; 11: 363-371Crossref PubMed Scopus (22) Google Scholar, 21So S. Adachi N. Lieber M.R. Koyama H. J. Biol. Chem. 2004; 279: 55433-55442Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). However, is this marked is caused by the increased of HR the increase in the of recombinogenic for HR, we to that Blm plays a critical role in the of HR. HR Ig gene conversion and gene targeting. It that HR reaction is associated with the formation of the whereas both are initiated by enzyme-mediated DNA activation-induced cytidine abasic and we are to the function of Blm in HR by Blm as a factor in the formation of the HJ in the of replication that Blm is required for Ig gene diverged segments are used as a donor In BLM−/− cells can HR-mediated repair with a level HR is out between sequences, sister results that Blm is required for recombination between diverged sequences not for HR between sequences. This idea was by that the of Blm the frequency of gene targeting to a as the number of heterologous sequences the DSB increased we showed that the limited of homologous is used in BLM−/− cells suggesting that Blm facilitates homologous of HR. therefore that Blm promotes homologous and in HR is sequence between donor and sequences. A between donor and sequences with HR in the following the with strand invasion into the homologous donor sequences and with the formation of the D-loop structure. the strongly the to in both Blm can the of the on HR. In the of HR, DNA are processed into 3′ single-stranded DNA by as well as by DNA J. P. Proc. Natl. Acad. Sci. U.S.A. 2008; PubMed Scopus Google Scholar, S. J.R. C. Genes 2008; 22: PubMed Scopus Google Scholar, E. H. A. Y. Takeda S. DNA 2006; PubMed Scopus Google Scholar, S. K. Y. Mol. Cell. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, Cell. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). have the of DSB end in budding the and followed by by and which with Sgs1, the yeast of Blm G. Cell. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, L.S. Nature. 2008; PubMed Scopus Google Scholar). a is that Blm facilitate the of and the resulting 3′ to strand invasion in the of the heterologous 3′ O. M. Mol. Cell. Biol. 1999; 19: PubMed Scopus (76) Google Scholar). This the role of Blm in the of gene targeting Blm facilitate D-loop formation by the of the 3′ The of the heterologous 3′ end can out by the and the helicase in yeast F. Haber J.E. Mol. Cell. Biol. PubMed Scopus Google Scholar) and by the in cells K. Y. Hatanaka A. Sonoda E. H. Adachi N. Y. Koyama H. Jasin M. Takeda S. Mol. Cell. Biol. PubMed Scopus Google Scholar). An not is that Blm the D-loop and DNA This model with the on gene targeting and Ig gene In both the heterologous sequences strongly the D-loop Blm the of the heterologous sequences on HR. This idea is supported by the by J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), in which that human Blm D-loop formation by on DNA in This is supported by the in in a defect in DNA repair synthesis in the SDSA DNA synthesis (15Adams M.D. McVey M. Sekelsky J.J. Science. 2003; 299: 265-267Crossref PubMed Scopus (208) Google Scholar, 16McVey M. Larocque J.R. Adams M.D. Sekelsky J.J. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 15694-15699Crossref PubMed Scopus (76) Google Scholar). In addition, a biochemical from that DmBlm strand suggesting the role of Blm to facilitate SDSA Nucleic Acids Res. 2007; PubMed Scopus Google Scholar). In summary, Blm can increase the of HR between diverged homologous sequences by promoting both the of DSBs and the formation of showed that Blm promotes HR between diverged homologous sequences through an ATPase-independent the of DNA in is by a reaction between human Blm and even in the of J. P. Proc. Natl. Acad. Sci. U.S.A. 2008; PubMed Scopus Google Scholar), this for the ATPase-independent of HR in In addition, the of the D-loop by Blm for the ATPase-independent This idea is supported by the by J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), which that human Blm can D-loop formation through an ATPase-independent in a biochemical showed that DmBlm strand by an ATPase-independent Nucleic Acids Res. 2007; PubMed Scopus Google Scholar), the that Blm promotes strand and results demonstrate that Blm can promote HR of Ig V This reaction plays a role does recombination in the of in and such as and (reviewed in D. X. Rev. 2000; PubMed Google and Nat. Rev. 2002; PubMed Scopus Google Scholar). HR to in Blm has to promote HR between diverged homologous sequences in In to Ig V Blm-dependent of HR to to such as and the DSBs (reviewed in Ref. Y. Cancer. 2006; PubMed Scopus Google Scholar). 3′ by are to homology search and D-loop heterologous sequences at DSBs with HR. The that the Blm-dependent of HR for the of cells to (17Kohzaki M. Hatanaka A. Sonoda E. Yamazoe M. Kikuchi K. Vu Trung N. Szüts D. Sale J.E. Shinagawa H. Watanabe M. Takeda S. Mol. Cell. Biol. 2007; 27: 2812-2820Crossref PubMed Scopus (39) Google Scholar, M. Seki M. Kawabe Y. Inoue E. T. Kato G. Yoshimura A. Tada S. Enomoto T. Biochem. Res. 2007; PubMed Scopus Google Scholar). M. Y. S. A. S. A. and for with