布盧姆綜合症蛋白

布盧姆綜合症蛋白（Bloom syndrome protein），係一種由BLM基因編碼的人類蛋白質，在布盧姆綜合症患者體內不表達。 布盧姆綜合症基因編碼的產物和RecQ（英语：RecQ）家族的DExH盒包含DNA解旋酶有關聯，同時有DNA刺激ATP酶和ATP依賴性DNA解旋酶活性。布盧姆綜合症患者的DNA突變導致布盧姆綜合症蛋白的解旋酶模體損壞或發生改變，可能使得酶失去3'→5'解旋酶活性。正常的布盧姆綜合症蛋白還可能參與對不恰當的同源重組的抑制。 減數分裂的重組通常始於DNA雙鏈的斷裂（DNA double-strand break (DSB)）。在重組中，DNA斷裂區的5'端鏈的前段部分會通過一個名爲切除（resection）的過程被切去。在鏈插入的過程中，自由的3'端DNA會插入同源染色體未斷裂的相應區域。在鏈插入後，會通過不同的途徑發生交叉互換發生（crossover，縮寫爲C0）或交叉互換不發生（non-crossover，縮寫爲NCO）的重組（具體可參見條目基因重組）。 芽殖酵母釀酒酵母（S.cerevisiae）編碼一種與布盧姆綜合症蛋白同源的蛋白，名爲Sgs1（英语：Sgs1）（小生長抑制物1，Small growth suppressor 1）。Sgs1係一種在同源重組過程中的DNA修復中發揮作用的解旋酶。Sgs1解旋酶可能是釀酒酵母減數分裂過程中的大部分重組事件的調控物質。在正常的減數分裂過程中，Sgs1負責介導交叉互換不發生或發生霍利迪交叉的分子的重組，後一種情況的分子發生的是交叉互換發生的重組。 在植物擬南芥（A.thaliana）體內，布盧姆綜合症蛋白的同源解旋酶是減數分裂中交叉互換發生的重組進行的主要抑制物。這類解旋酶替換了插入鏈，使得它能與其它的黏性3'端發生退火，通過上述的SDSA過程使得交叉互換不發生的重組發生。根據估計，只有4%的DNA雙鏈斷裂（DSB）以交叉互換發生的重組爲結果。Sequela-Arnaud等人認爲交叉互換發生的重組受限是因爲交叉互換發生的重組（CO）長期成本——交叉互換發生的重組會打亂自然選擇選出的有利的基因。 布盧姆綜合症蛋白可與以下蛋白質發生交互作用： 運動失調性毛細血管擴張症突變蛋白（英语：Ataxia telangiectasia mutated）（ATM） CHAF1A（英语：CHAF1A） CHEK1（英语：CHEK1） FANCM（英语：FANCM） FEN1（英语：Flap structure-specific endonuclease 1） H2AFX（英语：H2AFX） MLH1（英语：MLH1） P53 RAD51L3（英语：RAD51L3） RAD51 RPA1（英语：Replication protein A1） TOP3A（英语：TOP3A） TP53BP1（英语：TP53BP1） WRN（英语：Werner syndrome ATP-dependent helicase） XRCC2（英语：XRCC2） Karow JK, Chakraverty RK, Hickson ID. The Bloom's syndrome gene product is a 3'-5' DNA helicase. J Biol Chem. January 1998, 272 (49): 30611–4. PMID 9388193. doi:10.1074/jbc.272.49.30611.  Bloom syndrome. Genetics Home Reference. NIH. [19 March 2013]. （原始内容存档于2016-07-27）.  De Muyt A, Jessop L, Kolar E, Sourirajan A, Chen J, Dayani Y, Lichten M. BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism. Mol. Cell. 2012, 46 (1): 43–53. PMC 3328772 . PMID 22500736. doi:10.1016/j.molcel.2012.02.020.  Séguéla-Arnaud M, Crismani W, Larchevêque C, Mazel J, Froger N, Choinard S, Lemhemdi A, Macaisne N, Van Leene J, Gevaert K, De Jaeger G, Chelysheva L, Mercier R. Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM. Proc. Natl. Acad. Sci. U.S.A. 2015, 112 (15): 4713–8. PMC 4403193 . PMID 25825745. doi:10.1073/pnas.1423107112.  Crismani W, Girard C, Froger N, Pradillo M, Santos JL, Chelysheva L, Copenhaver GP, Horlow C, Mercier R. FANCM limits meiotic crossovers. Science. 2012, 336 (6088): 1588–90. PMID 22723424. doi:10.1126/science.1220381.  Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. April 2000, 14 (8): 927–39. PMC 316544 . PMID 10783165. doi:10.1101/gad.14.8.927.  Beamish H, Kedar P, Kaneko H, Chen P, Fukao T, Peng C, Beresten S, Gueven N, Purdie D, Lees-Miller S, Ellis N, Kondo N, Lavin MF. Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM. J. Biol. Chem. August 2002, 277 (34): 30515–23. PMID 12034743. doi:10.1074/jbc.M203801200.  Jiao R, Bachrati CZ, Pedrazzi G, Kuster P, Petkovic M, Li JL, Egli D, Hickson ID, Stagljar I. Physical and functional interaction between the Bloom's syndrome gene product and the largest subunit of chromatin assembly factor 1. Mol. Cell. Biol. June 2004, 24 (11): 4710–9. PMC 416397 . PMID 15143166. doi:10.1128/MCB.24.11.4710-4719.2004.  Sengupta S, Robles AI, Linke SP, Sinogeeva NI, Zhang R, Pedeux R, Ward IM, Celeste A, Nussenzweig A, Chen J, Halazonetis TD, Harris CC. Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest. J. Cell Biol. September 2004, 166 (6): 801–13. PMC 2172115 . PMID 15364958. doi:10.1083/jcb.200405128.  Deans AJ, West SC. FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Mol. Cell. 24 December 2009, 36 (6): 943–53. PMID 20064461. doi:10.1016/j.molcel.2009.12.006.  Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM. Stimulation of flap endonuclease-1 by the Bloom's syndrome protein. J. Biol. Chem. March 2004, 279 (11): 9847–56. PMID 14688284. doi:10.1074/jbc.M309898200.  Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP. Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha. Nucleic Acids Res. August 2001, 29 (15): 3172–80. PMC 55826 . PMID 11470874. doi:10.1093/nar/29.15.3172.  Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J. The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair. J. Biol. Chem. August 2001, 276 (32): 30031–5. PMID 11325959. doi:10.1074/jbc.M009664200.  Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I. Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Res. November 2001, 29 (21): 4378–86. PMC 60193 . PMID 11691925. doi:10.1093/nar/29.21.4378.  Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC. Functional interaction of p53 and BLM DNA helicase in apoptosis. J. Biol. Chem. August 2001, 276 (35): 32948–55. PMID 11399766. doi:10.1074/jbc.M103298200.  Garkavtsev IV, Kley N, Grigorian IA, Gudkov AV. The Bloom syndrome protein interacts and cooperates with p53 in regulation of transcription and cell growth control. Oncogene. December 2001, 20 (57): 8276–80. PMID 11781842. doi:10.1038/sj.onc.1205120.  Yang Q, Zhang R, Wang XW, Spillare EA, Linke SP, Subramanian D, Griffith JD, Li JL, Hickson ID, Shen JC, Loeb LA, Mazur SJ, Appella E, Brosh RM, Karmakar P, Bohr VA, Harris CC. The processing of Holliday junctions by BLM and WRN helicases is regulated by p53. J. Biol. Chem. August 2002, 277 (35): 31980–7. PMID 12080066. doi:10.1074/jbc.M204111200.  Braybrooke JP, Li JL, Wu L, Caple F, Benson FE, Hickson ID. Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D). J. Biol. Chem. November 2003, 278 (48): 48357–66. PMID 12975363. doi:10.1074/jbc.M308838200.  Wu L, Davies SL, Levitt NC, Hickson ID. Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. J. Biol. Chem. June 2001, 276 (22): 19375–81. PMID 11278509. doi:10.1074/jbc.M009471200.  Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA. Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity. J. Biol. Chem. August 2000, 275 (31): 23500–8. PMID 10825162. doi:10.1074/jbc.M001557200.  Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J. Biol. Chem. October 2002, 277 (43): 41110–9. PMID 12181313. doi:10.1074/jbc.M205396200.  Moens PB, Kolas NK, Tarsounas M, Marcon E, Cohen PE, Spyropoulos B. The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination. J. Cell. Sci. April 2002, 115 (Pt 8): 1611–22. PMID 11950880.  Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID. The Bloom's syndrome gene product interacts with topoisomerase III. J. Biol. Chem. March 2000, 275 (13): 9636–44. PMID 10734115. doi:10.1074/jbc.275.13.9636.  Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA. Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability. Hum. Mol. Genet. June 2001, 10 (12): 1287–98. PMID 11406610. doi:10.1093/hmg/10.12.1287.  von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM, Hickson ID, Bohr VA. Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. J. Biol. Chem. June 2002, 277 (24): 22035–44. PMID 11919194. doi:10.1074/jbc.M200914200.  Woo LL, Onel K, Ellis NA. The broken genome: genetic and pharmacologic approaches to breaking DNA. Ann. Med. 2007, 39 (3): 208–18. PMID 17457718. doi:10.1080/08035250601167136.  McDaniel LD, Schultz RA. Elevated sister chromatid exchange phenotype of Bloom syndrome cells is complemented by human chromosome 15. Proc. Natl. Acad. Sci. U.S.A. 1992, 89 (17): 7968–72. PMC 49836 . PMID 1518822. doi:10.1073/pnas.89.17.7968.  Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell. 1995, 83 (4): 655–66. PMID 7585968. doi:10.1016/0092-8674(95)90105-1.  German J, Roe AM, Leppert MF, Ellis NA. Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proc. Natl. Acad. Sci. U.S.A. 1994, 91 (14): 6669–73. PMC 44264 . PMID 8022833. doi:10.1073/pnas.91.14.6669.  Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, Amor-Guéret M. Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome. Hum. Mol. Genet. 1998, 6 (9): 1427–34. PMID 9285778. doi:10.1093/hmg/6.9.1427.  Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N. BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal. Biochem. Biophys. Res. Commun. 1997, 240 (2): 348–53. PMID 9388480. doi:10.1006/bbrc.1997.7648.  Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID. The Bloom's syndrome gene product interacts with topoisomerase III. J. Biol. Chem. 2000, 275 (13): 9636–44. PMID 10734115. doi:10.1074/jbc.275.13.9636.  Yankiwski V, Marciniak RA, Guarente L, Neff NF. Nuclear structure in normal and Bloom syndrome cells. Proc. Natl. Acad. Sci. U.S.A. 2000, 97 (10): 5214–9. PMC 25808 . PMID 10779560. doi:10.1073/pnas.090525897.  Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000, 14 (8): 927–39. PMC 316544 . PMID 10783165. doi:10.1101/gad.14.8.927.  Karow JK, Constantinou A, Li JL, West SC, Hickson ID. The Bloom's syndrome gene product promotes branch migration of Holliday junctions. Proc. Natl. Acad. Sci. U.S.A. 2000, 97 (12): 6504–8. PMC 18638 . PMID 10823897. doi:10.1073/pnas.100448097.  Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA. Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity. J. Biol. Chem. 2000, 275 (31): 23500–8. PMID 10825162. doi:10.1074/jbc.M001557200.  Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Guéret M. Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase. Oncogene. 2000, 19 (23): 2731–8. PMID 10851073. doi:10.1038/sj.onc.1203595.  Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda N, Benslimane A, Amor-Guéret M. Identification of a novel BLM missense mutation (2706T>C) in a Moroccan patient with Bloom's syndrome. Hum. Mutat. 2000, 15 (6): 584–5. PMID 10862105. doi:10.1002/1098-1004(200006)15:6<584::AID-HUMU28>3.0.CO;2-I.  Brosh RM, Karow JK, White EJ, Shaw ND, Hickson ID, Bohr VA. Potent inhibition of Werner and Bloom helicases by DNA minor groove binding drugs. Nucleic Acids Res. 2000, 28 (12): 2420–30. PMC 102731 . PMID 10871376. doi:10.1093/nar/28.12.2420.  Wu L, Davies SL, Levitt NC, Hickson ID. Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. J. Biol. Chem. 2001, 276 (22): 19375–81. PMID 11278509. doi:10.1074/jbc.M009471200.  Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J. The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair. J. Biol. Chem. 2001, 276 (32): 30031–5. PMID 11325959. doi:10.1074/jbc.M009664200.  Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC. Functional interaction of p53 and BLM DNA helicase in apoptosis. J. Biol. Chem. 2001, 276 (35): 32948–55. PMID 11399766. doi:10.1074/jbc.M103298200.  Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA. Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability. Hum. Mol. Genet. 2001, 10 (12): 1287–98. PMID 11406610. doi:10.1093/hmg/10.12.1287.  Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP. Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIα. Nucleic Acids Res. 2001, 29 (15): 3172–80. PMC 55826 . PMID 11470874. doi:10.1093/nar/29.15.3172.  GeneReviews/NCBI/NIH/UW entry on Bloom Syndrome （页面存档备份，存于互联网档案馆）