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BLM  -  Bloom syndrome, RecQ helicase-like

Homo sapiens

 
 
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Disease relevance of BLM

  • BLM-/- cells showed hypersensitivities to the genotoxic agents as well as ultraviolet (UV) light, in addition to a 10-fold increase in targeted integration rate and an 11-fold increase in SCE frequency [1].
  • We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors [2].
  • Of the five human RecQ helicases identified, three are associated with genetic disorders characterized by an elevated incidence of cancer or premature aging: Werner syndrome, Bloom syndrome, and Rothmund-Thomson syndrome [3].
  • BLM physically associates with ATR (ataxia telangiectasia and rad3(+) related) protein and is phosphorylated on two residues in the N-terminal domain, Thr-99 and Thr-122, by this kinase [4].
  • We show that, consistent with a role for BLM in protection of human cells against the toxicity associated with arrest of DNA replication, BS cells are hypersensitive to HU [4].
 

Psychiatry related information on BLM

 

High impact information on BLM

  • This suggests that defects in the suppression of rearrangements involving divergent, repeated sequences may underlie the genome instability seen in BLM and WRN patients and in cancer cases associated with defects in these genes [6].
  • Bloom syndrome is a disorder associated with genomic instability that causes affected people to be prone to cancer [7].
  • In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases [8].
  • A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping [8].
  • Sterility of Drosophila with mutations in the Bloom syndrome gene--complementation by Ku70 [9].
 

Chemical compound and disease context of BLM

 

Biological context of BLM

  • These results indicate that p53 and BLM functionally interact during resolution of stalled DNA replication forks and provide insight into the mechanism of genomic fidelity maintenance by these nuclear proteins [15].
  • Our findings suggest that BLM is part of a dynamic nuclear matrix-based complex that requires PML and functions during G2 in undamaged cells and recombinational repair after DNA damage [16].
  • We also find that the FA core complex is necessary for BLM phosphorylation and assembly in nuclear foci in response to crosslinked DNA [17].
  • BLM colocalizes with a select subset of telomeres in normal cells and with large telomeric clusters seen in simian virus 40-transformed normal fibroblasts [18].
  • BLM is likely to be part of a DNA surveillance mechanism operating during S phase [18].
 

Anatomical context of BLM

  • Moreover, BLM and WRN colocalized to nuclear foci in three human cell lines [19].
  • We produced WRN-/-, BLM-/- and WRN(-/-)/BLM(-/-) mutants in the chicken B-cell line DT40 [1].
  • Human males homozygous for BLM mutations are infertile and heterozygous individuals display increased frequencies of structural chromosome abnormalities in their spermatozoa [20].
  • Our antibodies raised against the C terminus of the human protein specifically recognize both mouse and human BLM in western blots of cell lines and in successive developmental stages of spermatocytes, but fail to detect BLM protein in a cell line with a C-terminally truncated protein [20].
  • Bone marrow cells from mice heterozygous for BLM mutation, BLM(Cin/+), transfected with BCR/ABL display increased sensitivity to cisplatin compared to those obtained from the wild-type littermates [21].
 

Associations of BLM with chemical compounds

  • Moreover, lymphoblastoid cell lines (LCLs) derived from BS donors are resistant to both gamma-radiation and doxorubicin-induced cell killing, and sensitivity can be restored by the stable expression of normal BLM [22].
  • Finally, we demonstrate that exposure to UVC and hydroxyurea treatment both induce BLM phosphorylation via an ATM-independent pathway [23].
  • The results demonstrate that BLM and WRN proteins exhibit similar sensitivity profiles to these DNA-binding ligands and are most potently inhibited by the structurally related minor groove binders distamycin A and netropsin (K(i) </=1 microM) [24].
  • The caspase 3 recognition sequence (412)TEVD(415) was verified by mutating aspartate 415 to glycine and showing that this mutation rendered BLM resistant to caspase 3 cleavage [25].
  • Here, we show that BCR/ABL tyrosine kinase, which also modulates DNA repair capacity, is associated with elevated expression of BLM [21].
 

Physical interactions of BLM

  • Biochemical experiments suggested that BLM resides in a nuclear matrix-bound complex in which association with hRAD51 may be direct [16].
  • BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination [15].
  • Amino acids 125 to 244 of Mus81 interact with the C-terminal region (amino acids 1,007-1,417) of BLM [26].
  • The C terminus of BLM interacts directly with MLH1 in the yeast-two hybrid assay; far Western analysis and co-immunoprecipitations confirmed the interaction [27].
 

Enzymatic interactions of BLM

  • Moreover, recombinant BLM was cleaved to 47- and 110-kDa fragments by caspase 3, but not caspase 6, in vitro [25].
  • Finally, we present data demonstrating that, in response to ionizing radiation, BLM protein is phosphorylated and accumulates through an ATM-dependent pathway [28].
  • We also demonstrate that BLM is directly phosphorylated at multiple sites in vitro by the mitotic cdc2 kinase, and identify two new sites of mitotic BLM phosphorylation: Ser-714 and Thr-766 [29].
  • In the presence of ATP, BLM is phosphorylated and dissociates from DNA in a strictly DNA-PKcs-dependent manner [30].
 

Co-localisations of BLM

  • BLM is found primarily in nuclear domain 10 except during S phase when it colocalizes with the Werner syndrome gene product, WRN, in the nucleolus [18].
  • Following camptothecin treatment, T99p-BLM colocalized with gamma-H2AX but not with Top3alpha or PML [31].
  • BLM co-localizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; co-localization increases in late S and G2/M when ALT is thought to occur [32].
 

Regulatory relationships of BLM

  • We show that the RAD51L3-XRCC2 complex stimulates BLM to disrupt synthetic 4-way junctions that model the Holliday junction [33].
  • Certain BLM mutants (C1055S or Delta133-237) that have a reduced ability to localize to the NBs when expressed in normal cells can impair the localization of wild type BLM to NBs and block p53-mediated apoptosis, suggesting a dominant-negative effect [22].
  • Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases [34].
  • Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification [35].
  • Functionally, BLM inhibited the exonuclease activity of WRN [19].
 

Other interactions of BLM

  • DNA-damaging agents that cause double strand breaks and a G2 delay induced BLM by a p53- and ataxia-telangiectasia mutated independent mechanism [16].
  • BLM localizes to promyelocytic leukemia protein (PML) nuclear bodies and is expressed during late S and G2 [16].
  • These BLM foci recruited BRCA1 and NBS1 [36].
  • We provide evidence that BLM and FANCD2 colocalise and co-immunoprecipitate following treatment with either DNA crosslinkers or agents inducing replication arrest [17].
  • These conditions, however, did not prevent the DNA damage response in BLM-ablated cells, suggesting a distinct role for WRN in DNA homeostasis in vivo [37].
  • SUV3 helicase ( SUPV3L1) was found to interact in vitro with BLM and WRN helicases
 

Analytical, diagnostic and therapeutic context of BLM

References

  1. Werner and Bloom helicases are involved in DNA repair in a complementary fashion. Imamura, O., Fujita, K., Itoh, C., Takeda, S., Furuichi, Y., Matsumoto, T. Oncogene (2002) [Pubmed]
  2. Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer. Wirtenberger, M., Frank, B., Hemminki, K., Klaes, R., Schmutzler, R.K., Wappenschmidt, B., Meindl, A., Kiechle, M., Arnold, N., Weber, B.H., Niederacher, D., Bartram, C.R., Burwinkel, B. Carcinogenesis (2006) [Pubmed]
  3. Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1. Sharma, S., Sommers, J.A., Choudhary, S., Faulkner, J.K., Cui, S., Andreoli, L., Muzzolini, L., Vindigni, A., Brosh, R.M. J. Biol. Chem. (2005) [Pubmed]
  4. Phosphorylation of the Bloom's syndrome helicase and its role in recovery from S-phase arrest. Davies, S.L., North, P.S., Dart, A., Lakin, N.D., Hickson, I.D. Mol. Cell. Biol. (2004) [Pubmed]
  5. Helicases and aging. Nakura, J., Ye, L., Morishima, A., Kohara, K., Miki, T. Cell. Mol. Life Sci. (2000) [Pubmed]
  6. SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Myung, K., Datta, A., Chen, C., Kolodner, R.D. Nat. Genet. (2001) [Pubmed]
  7. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Luo, G., Santoro, I.M., McDaniel, L.D., Nishijima, I., Mills, M., Youssoufian, H., Vogel, H., Schultz, R.A., Bradley, A. Nat. Genet. (2000) [Pubmed]
  8. The Bloom's syndrome gene product is homologous to RecQ helicases. Ellis, N.A., Groden, J., Ye, T.Z., Straughen, J., Lennon, D.J., Ciocci, S., Proytcheva, M., German, J. Cell (1995) [Pubmed]
  9. Sterility of Drosophila with mutations in the Bloom syndrome gene--complementation by Ku70. Kusano, K., Johnson-Schlitz, D.M., Engels, W.R. Science (2001) [Pubmed]
  10. Liblomycin-mediated DNA cleavage in human head and neck squamous carcinoma cells and purified DNA. Wassermann, K., Zwelling, L.A., Lown, J.W., Hartley, J.A., Nishikawa, K., Lin, J.R., Newman, R.A. Cancer Res. (1990) [Pubmed]
  11. The pattern of metastasis of human melanoma to the central nervous system is not influenced by integrin alpha(v)beta(3) expression. Küsters, B., Westphal, J.R., Smits, D., Ruiter, D.J., Wesseling, P., Keilholz, U., de Waal, R.M. Int. J. Cancer (2001) [Pubmed]
  12. An in vitro stimulation of the effects of chewing sugar-free and sugar-containing chewing gums on pH changes in dental plaque. Macpherson, L.M., Dawes, C. J. Dent. Res. (1993) [Pubmed]
  13. Comparative study of two neoadjuvant protocols (VBM and DDP-BLM) combined with radiation therapy in advanced head and neck cancer. Amichetti, M., Valentini, A. Journal of chemotherapy (Florence, Italy) (1989) [Pubmed]
  14. Cancer antigens are expressed in a carcinogen-transformed Bloom syndrome B-lymphoblastoid cell line. Shiraishi, Y., Soma, H. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  15. BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. Sengupta, S., Linke, S.P., Pedeux, R., Yang, Q., Farnsworth, J., Garfield, S.H., Valerie, K., Shay, J.W., Ellis, N.A., Wasylyk, B., Harris, C.C. EMBO J. (2003) [Pubmed]
  16. Regulation and localization of the Bloom syndrome protein in response to DNA damage. Bischof, O., Kim, S.H., Irving, J., Beresten, S., Ellis, N.A., Campisi, J. J. Cell Biol. (2001) [Pubmed]
  17. BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks. Pichierri, P., Franchitto, A., Rosselli, F. EMBO J. (2004) [Pubmed]
  18. Nuclear structure in normal and Bloom syndrome cells. Yankiwski, V., Marciniak, R.A., Guarente, L., Neff, N.F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. von Kobbe, C., Karmakar, P., Dawut, L., Opresko, P., Zeng, X., Brosh, R.M., Hickson, I.D., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  20. Expression and nuclear localization of BLM, a chromosome stability protein mutated in Bloom's syndrome, suggest a role in recombination during meiotic prophase. Moens, P.B., Freire, R., Tarsounas, M., Spyropoulos, B., Jackson, S.P. J. Cell. Sci. (2000) [Pubmed]
  21. BLM helicase is activated in BCR/ABL leukemia cells to modulate responses to cisplatin. Slupianek, A., Gurdek, E., Koptyra, M., Nowicki, M.O., Siddiqui, K.M., Groden, J., Skorski, T. Oncogene (2005) [Pubmed]
  22. Functional interaction of p53 and BLM DNA helicase in apoptosis. Wang, X.W., Tseng, A., Ellis, N.A., Spillare, E.A., Linke, S.P., Robles, A.I., Seker, H., Yang, Q., Hu, P., Beresten, S., Bemmels, N.A., Garfield, S., Harris, C.C. J. Biol. Chem. (2001) [Pubmed]
  23. Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition. Ababou, M., Dumaire, V., Lécluse, Y., Amor-Guéret, M. Oncogene (2002) [Pubmed]
  24. Potent inhibition of werner and bloom helicases by DNA minor groove binding drugs. Brosh, R.M., Karow, J.K., White, E.J., Shaw, N.D., Hickson, I.D., Bohr, V.A. Nucleic Acids Res. (2000) [Pubmed]
  25. Selective cleavage of BLM, the bloom syndrome protein, during apoptotic cell death. Bischof, O., Galande, S., Farzaneh, F., Kohwi-Shigematsu, T., Campisi, J. J. Biol. Chem. (2001) [Pubmed]
  26. BLM helicase facilitates Mus81 endonuclease activity in human cells. Zhang, R., Sengupta, S., Yang, Q., Linke, S.P., Yanaihara, N., Bradsher, J., Blais, V., McGowan, C.H., Harris, C.C. Cancer Res. (2005) [Pubmed]
  27. The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair. Langland, G., Kordich, J., Creaney, J., Goss, K.H., Lillard-Wetherell, K., Bebenek, K., Kunkel, T.A., Groden, J. J. Biol. Chem. (2001) [Pubmed]
  28. ATM-dependent phosphorylation and accumulation of endogenous BLM protein in response to ionizing radiation. Ababou, M., Dutertre, S., Lécluse, Y., Onclercq, R., Chatton, B., Amor-Guéret, M. Oncogene (2000) [Pubmed]
  29. The Bloom syndrome helicase is a substrate of the mitotic Cdc2 kinase. Bayart, E., Dutertre, S., Jaulin, C., Guo, R.B., Xi, X.G., Amor-Guéret, M. Cell Cycle (2006) [Pubmed]
  30. Possible anti-recombinogenic role of Bloom's syndrome helicase in double-strand break processing. Onclercq-Delic, R., Calsou, P., Delteil, C., Salles, B., Papadopoulo, D., Amor-Guéret, M. Nucleic Acids Res. (2003) [Pubmed]
  31. Phosphorylation of BLM, dissociation from topoisomerase IIIalpha, and colocalization with gamma-H2AX after topoisomerase I-induced replication damage. Rao, V.A., Fan, A.M., Meng, L., Doe, C.F., North, P.S., Hickson, I.D., Pommier, Y. Mol. Cell. Biol. (2005) [Pubmed]
  32. Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2. Lillard-Wetherell, K., Machwe, A., Langland, G.T., Combs, K.A., Behbehani, G.K., Schonberg, S.A., German, J., Turchi, J.J., Orren, D.K., Groden, J. Hum. Mol. Genet. (2004) [Pubmed]
  33. Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D). Braybrooke, J.P., Li, J.L., Wu, L., Caple, F., Benson, F.E., Hickson, I.D. J. Biol. Chem. (2003) [Pubmed]
  34. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. Opresko, P.L., von Kobbe, C., Laine, J.P., Harrigan, J., Hickson, I.D., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  35. Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. Eladad, S., Ye, T.Z., Hu, P., Leversha, M., Beresten, S., Matunis, M.J., Ellis, N.A. Hum. Mol. Genet. (2005) [Pubmed]
  36. Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks. Davalos, A.R., Campisi, J. J. Cell Biol. (2003) [Pubmed]
  37. Werner protein protects nonproliferating cells from oxidative DNA damage. Szekely, A.M., Bleichert, F., Nümann, A., Van Komen, S., Manasanch, E., Ben Nasr, A., Canaan, A., Weissman, S.M. Mol. Cell. Biol. (2005) [Pubmed]
  38. Stimulation of flap endonuclease-1 by the Bloom's syndrome protein. Sharma, S., Sommers, J.A., Wu, L., Bohr, V.A., Hickson, I.D., Brosh, R.M. J. Biol. Chem. (2004) [Pubmed]
  39. BLM is an early responder to DNA double-strand breaks. Karmakar, P., Seki, M., Kanamori, M., Hashiguchi, K., Ohtsuki, M., Murata, E., Inoue, E., Tada, S., Lan, L., Yasui, A., Enomoto, T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  40. ATR and ATM-dependent movement of BLM helicase during replication stress ensures optimal ATM activation and 53BP1 focus formation. Davalos, A.R., Kaminker, P., Hansen, R.K., Campisi, J. Cell Cycle (2004) [Pubmed]
  41. Oligomeric ring structure of the Bloom's syndrome helicase. Karow, J.K., Newman, R.H., Freemont, P.S., Hickson, I.D. Curr. Biol. (1999) [Pubmed]
  42. The Bloom's syndrome gene product is a 3'-5' DNA helicase. Karow, J.K., Chakraverty, R.K., Hickson, I.D. J. Biol. Chem. (1997) [Pubmed]
 
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