布卢姆综合症蛋白

布卢姆综合症蛋白（Bloom syndrome protein），系一种由BLM基因编码的人类蛋白质，在布卢姆综合症患者体内不表达^[1]。

布卢姆综合征蛋白 BLM
有效结构 PDB 直系同源检索：PDBe, RCSB PDB查询代码列表 2KV2, 2MH9, 2RRD, 3WE2, 3WE3, 4CDG, 4CGZ, 4O3M
标识
代号	BLM; BS; RECQ2; RECQL2; RECQL3
扩展标识	遗传学：604610 鼠基因：1328362 同源基因：47902 ChEMBL: 1293237 GeneCards: BLM Gene
EC编号	3.6.4.12
基因本体论描述 分子功能 · bubble DNA binding · p53 binding · single-stranded DNA binding · ATP-dependent DNA helicase activity · helicase activity · protein binding · ATP binding · ATP-dependent helicase activity · four-way junction helicase activity · ATPase activity · annealing helicase activity · ATP-dependent 3'-5' DNA helicase activity · G-quadruplex DNA binding 细胞成分 · nuclear chromosome · chromosome, telomeric region · lateral element · male germ cell nucleus · nucleus · nucleoplasm · replication fork · nucleolus · cytoplasm · nuclear matrix · PML body · pronucleus 生物过程 · regulation of cyclin-dependent protein serine/threonine kinase activity · telomere maintenance · double-strand break repair via homologous recombination · DNA double-strand break processing · DNA strand renaturation · DNA repair · DNA recombination · cellular response to DNA damage stimulus · mitotic G2 DNA damage checkpoint · response to X-ray · protein sumoylation · replication fork processing · DNA duplex unwinding · post-translational protein modification · cellular protein metabolic process · positive regulation of transcription, DNA-templated · negative regulation of DNA recombination · negative regulation of mitotic recombination · alpha-beta T cell differentiation · positive regulation of alpha-beta T cell proliferation · replication fork protection · regulation of binding · protein oligomerization · negative regulation of cell division · negative regulation of thymocyte apoptotic process · cellular response to ionizing radiation · cellular response to hydroxyurea · cellular response to camptothecin Sources: Amigo / QuickGO
直系同源体
物种	人类	小鼠
Entrez	641	12144
Ensembl	ENSG00000197299	ENSMUSG00000030528
UniProt	P54132	O88700
mRNA序列	NM_000057	NM_001042527
蛋白序列	NP_000048	NP_001035992
基因位置	Chr 15: 90.72 – 90.82 Mb	Chr 7: 80.45 – 80.54 Mb
PubMed查询	[1]	[2]
查 论 编

布卢姆综合症基因编码的产物和RecQ（英语：RecQ）家族的DExH盒包含DNA解旋酶有关联，同时有DNA刺激ATP酶和ATP依赖性DNA解旋酶活性。布卢姆综合症患者的DNA突变导致布卢姆综合症蛋白的解旋酶模体损坏或发生改变，可能使得酶失去3'→5'解旋酶活性。正常的布卢姆综合症蛋白还可能参与对不恰当的同源重组的抑制^[2]。

减数分裂

一个正常的减数分裂模型，以一个双链DNA分子断裂开始，紧随与同源染色体的配对，以及介导重组修复过程的链插入过程。对DNA分子的断裂的修复可以使得交叉互换发生（crossover，缩写为C0），也可能使得交叉互换不发生（non-crossover，缩写为NCO）。一个名为“双霍利迪交叉”（Double Holliday Junction (DHJ)）的模型可以概述发生交叉互换的重组（CO）的情况，如右上方所示。不发生交叉互换的重组（NCO）基本可由合成依赖链退火（Synthesis Dependent Strand Annealing (SDSA)）模型来解释，如左上方所示。大部分的重组都符合SDSA模型

减数分裂的重组通常始于DNA双链的断裂（DNA double-strand break (DSB)）。在重组中，DNA断裂区的5'端链的前段部分会通过一个名为切除（resection）的过程被切去。在链插入的过程中，自由的3'端DNA会插入同源染色体未断裂的相应区域。在链插入后，会通过不同的途径发生交叉互换发生（crossover，缩写为C0）或交叉互换不发生（non-crossover，缩写为NCO）的重组（具体可参见条目基因重组）。

芽殖酵母酿酒酵母（S.cerevisiae）编码一种与布卢姆综合症蛋白同源的蛋白，名为Sgs1（英语：Sgs1）（小生长抑制物1，Small growth suppressor 1）。Sgs1系一种在同源重组过程中的DNA修复中发挥作用的解旋酶。Sgs1解旋酶可能是酿酒酵母减数分裂过程中的大部分重组事件的调控物质^[3]。在正常的减数分裂过程中，Sgs1负责介导交叉互换不发生或发生霍利迪交叉的分子的重组，后一种情况的分子发生的是交叉互换发生的重组^[3]。

在植物拟南芥（A.thaliana）体内，布卢姆综合症蛋白的同源解旋酶是减数分裂中交叉互换发生的重组进行的主要抑制物^[4]。这类解旋酶替换了插入链，使得它能与其它的黏性3'端发生退火，通过上述的SDSA过程使得交叉互换不发生的重组发生。根据估计，只有4%的DNA双链断裂（DSB）以交叉互换发生的重组为结果^[5]。Sequela-Arnaud等人^[4]认为交叉互换发生的重组受限是因为交叉互换发生的重组（CO）长期成本——交叉互换发生的重组会打乱自然选择选出的有利的基因。

交互作用

布卢姆综合症蛋白可与以下蛋白质发生交互作用：

• 运动失调性毛细血管扩张症突变蛋白（英语：Ataxia telangiectasia mutated）（ATM）^[6][7]
• CHAF1A（英语：CHAF1A）^[8]
• CHEK1（英语：CHEK1）^[9]
• FANCM（英语：FANCM）^[10]
• FEN1（英语：Flap structure-specific endonuclease 1）^[11]
• H2AFX（英语：H2AFX）^[9]
• MLH1（英语：MLH1）^{[6][12][13][14]}
• P53^{[9][15][16][17]}
• RAD51L3（英语：RAD51L3）^[18]
• RAD51^[19]
• RPA1（英语：Replication protein A1）^[20][21][22]
• TOP3A（英语：TOP3A）^{[12][20][23][24]}
• TP53BP1（英语：TP53BP1）^[9]
• WRN（英语：Werner syndrome ATP-dependent helicase）^[25]
• XRCC2（英语：XRCC2）^[18]

参考

1. 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.
2. Bloom syndrome. Genetics Home Reference. NIH. [19 March 2013]. （原始内容存档于2016-07-27）.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.

拓展阅读

• 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.

外部链接

• GeneReviews/NCBI/NIH/UW entry on Bloom Syndrome （页面存档备份，存于互联网档案馆）