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Bloom syndrome protein

From Wikipedia, the free encyclopedia
BLM
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBLM, BS, RECQ2, RECQL2, RECQL3, Bloom syndrome RecQ like helicase, BLM RecQ like helicase, MGRISCE1
External IDsOMIM: 604610; MGI: 1328362; HomoloGene: 47902; GeneCards: BLM; OMA:BLM - orthologs
Orthologs
SpeciesHumanMouse
Entrez

641

12144

Ensembl

ENSG00000197299

ENSMUSG00000030528

UniProt

P54132

O88700

RefSeq (mRNA)

NM_000057
NM_001287246
NM_001287247
NM_001287248

NM_001042527
NM_007550

RefSeq (protein)

NP_000048
NP_001274175
NP_001274176
NP_001274177
NP_001274177.1

NP_001035992
NP_031576

Location (UCSC)Chr 15: 90.72 – 90.82 MbChr 7: 80.1 – 80.18 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.[5]

The Bloom syndrome gene product is related to the RecQ subset of DExH box-containing DNA helicases and has both DNA-stimulated ATPase and ATP-dependent DNA helicase activities. Mutations causing Bloom syndrome delete or alter helicase motifs and may disable the 3' → 5' helicase activity. The normal protein may act to suppress inappropriate homologous recombination.[6]

Meiosis

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A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken. After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and bottom of Figure in this section).

The budding yeast Saccharomyces cerevisiae encodes an ortholog of the Bloom syndrome (BLM) protein that is designated Sgs1 (Small growth suppressor 1). Sgs1(BLM) is a helicase that functions in homologous recombinational repair of DSBs. The Sgs1(BLM) helicase appears to be a central regulator of most of the recombination events that occur during S. cerevisiae meiosis.[7] During normal meiosis Sgs1(BLM) is responsible for directing recombination towards the alternate formation of either early NCOs or Holliday junction joint molecules, the latter being subsequently resolved as COs.[7]

In the plant Arabidopsis thaliana, homologs of the Sgs1(BLM) helicase act as major barriers to meiotic CO formation.[8] These helicases are thought to displace the invading strand allowing its annealing with the other 3’overhang end of the DSB, leading to NCO recombinant formation by a process called synthesis dependent strand annealing (SDSA) (see Genetic recombination and Figure in this section). It is estimated that only about 4% of DSBs are repaired by CO recombination.[9] Sequela-Arnaud et al.[8] suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.

DNA repair and apoptosis

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Bloom syndrome protein facilitates DNA repair when cells are stressed by agents that cause DNA damage, specifically when DNA replication forks are stalled. Damage present during S phase of the cell cycle causes Bloom syndrome protein to rapidly form foci with gamma H2AFX protein at replication forks that develop DNA breaks.[10] These BLM foci then recruit repair complexes composed of BRCA1 and NBS1 proteins to the stalled replication forks. In addition to its role in repairing DNA damages, Bloom syndrome protein facilitates apoptosis (programmed cell death), a process dependent on p53 protein when cells are stressed by agents that cause unrepairable DNA damage, particularly damage that causes stalled DNA replication forks.[10][11]

Both DNA repair and apoptosis are enzymatic processes necessary for maintaining genome integrity in humans. Cells that are deficient in DNA repair tend to accumulate DNA damages, and when such cells are also defective in apoptosis they tend to survive even though excessive DNA damage is present.[12] Replication of DNA in such cells tends to lead to mutations and such mutations may cause cancer. Thus Bloom syndrome protein appears to have two roles related to the prevention of cancer, where the first role is to promote repair of a specific class of damages and the second role is to induce apoptosis if the level of such DNA damage is beyond the cell's repair capability[12]

Interactions

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Bloom syndrome protein has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000197299 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030528 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Karow JK, Chakraverty RK, Hickson ID (January 1998). "The Bloom's syndrome gene product is a 3'-5' DNA helicase". J Biol Chem. 272 (49): 30611–4. doi:10.1074/jbc.272.49.30611. PMID 9388193.
  6. ^ "Bloom syndrome". Genetics Home Reference. NIH. Retrieved 19 March 2013.
  7. ^ a b De Muyt A, Jessop L, Kolar E, Sourirajan A, Chen J, Dayani Y, Lichten M (2012). "BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism". Mol. Cell. 46 (1): 43–53. doi:10.1016/j.molcel.2012.02.020. PMC 3328772. PMID 22500736.
  8. ^ a b 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 (2015). "Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM". Proc. Natl. Acad. Sci. U.S.A. 112 (15): 4713–8. Bibcode:2015PNAS..112.4713S. doi:10.1073/pnas.1423107112. hdl:1854/LU-6829814. PMC 4403193. PMID 25825745.
  9. ^ Crismani W, Girard C, Froger N, Pradillo M, Santos JL, Chelysheva L, Copenhaver GP, Horlow C, Mercier R (2012). "FANCM limits meiotic crossovers". Science. 336 (6088): 1588–90. Bibcode:2012Sci...336.1588C. doi:10.1126/science.1220381. PMID 22723424. S2CID 14570996.
  10. ^ a b Davalos AR, Campisi J (September 2003). "Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks". J Cell Biol. 162 (7): 1197–209. doi:10.1083/jcb.200304016. PMC 2173967. PMID 14517203.
  11. ^ a b 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 (August 2001). "Functional interaction of p53 and BLM DNA helicase in apoptosis". J. Biol. Chem. 276 (35): 32948–55. doi:10.1074/jbc.M103298200. PMID 11399766.
  12. ^ a b Bernstein C, Bernstein H, Payne CM, Garewal H (June 2002). "DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis". Mutat Res. 511 (2): 145–78. Bibcode:2002MRRMR.511..145B. doi:10.1016/s1383-5742(02)00009-1. PMID 12052432.
  13. ^ a b Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (April 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. doi:10.1101/gad.14.8.927. PMC 316544. PMID 10783165.
  14. ^ 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 (August 2002). "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM". J. Biol. Chem. 277 (34): 30515–23. doi:10.1074/jbc.M203801200. PMID 12034743.
  15. ^ Jiao R, Bachrati CZ, Pedrazzi G, Kuster P, Petkovic M, Li JL, Egli D, Hickson ID, Stagljar I (June 2004). "Physical and functional interaction between the Bloom's syndrome gene product and the largest subunit of chromatin assembly factor 1". Mol. Cell. Biol. 24 (11): 4710–9. doi:10.1128/MCB.24.11.4710-4719.2004. PMC 416397. PMID 15143166.
  16. ^ a b c d Sengupta S, Robles AI, Linke SP, Sinogeeva NI, Zhang R, Pedeux R, Ward IM, Celeste A, Nussenzweig A, Chen J, Halazonetis TD, Harris CC (September 2004). "Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest". J. Cell Biol. 166 (6): 801–13. doi:10.1083/jcb.200405128. PMC 2172115. PMID 15364958.
  17. ^ Deans AJ, West SC (24 December 2009). "FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia". Mol. Cell. 36 (6): 943–53. doi:10.1016/j.molcel.2009.12.006. PMID 20064461.
  18. ^ Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM (March 2004). "Stimulation of flap endonuclease-1 by the Bloom's syndrome protein". J. Biol. Chem. 279 (11): 9847–56. doi:10.1074/jbc.M309898200. PMID 14688284.
  19. ^ Shastri, Vivek; Subramanian, Veena (7 September 2021). "A novel cell-cycle-regulated interaction of the Bloom syndrome helicase BLM with Mcm6 controls replication-linked processes". Nucleic Acids Research. 49 (15): 8699–8713. doi:10.1093/nar/gkab663. PMC 8421143. PMID 34370039.
  20. ^ a b Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP (August 2001). "Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha". Nucleic Acids Res. 29 (15): 3172–80. doi:10.1093/nar/29.15.3172. PMC 55826. PMID 11470874.
  21. ^ Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J (August 2001). "The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair". J. Biol. Chem. 276 (32): 30031–5. doi:10.1074/jbc.M009664200. PMID 11325959.
  22. ^ Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I (November 2001). "Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1". Nucleic Acids Res. 29 (21): 4378–86. doi:10.1093/nar/29.21.4378. PMC 60193. PMID 11691925.
  23. ^ Garkavtsev IV, Kley N, Grigorian IA, Gudkov AV (December 2001). "The Bloom syndrome protein interacts and cooperates with p53 in regulation of transcription and cell growth control". Oncogene. 20 (57): 8276–80. doi:10.1038/sj.onc.1205120. PMID 11781842. S2CID 13084911.
  24. ^ 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 (August 2002). "The processing of Holliday junctions by BLM and WRN helicases is regulated by p53". J. Biol. Chem. 277 (35): 31980–7. doi:10.1074/jbc.M204111200. hdl:10026.1/10341. PMID 12080066.
  25. ^ a b Braybrooke JP, Li JL, Wu L, Caple F, Benson FE, Hickson ID (November 2003). "Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D)". J. Biol. Chem. 278 (48): 48357–66. doi:10.1074/jbc.M308838200. hdl:10026.1/10297. PMID 12975363.
  26. ^ Wu L, Davies SL, Levitt NC, Hickson ID (June 2001). "Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51". J. Biol. Chem. 276 (22): 19375–81. doi:10.1074/jbc.M009471200. PMID 11278509.
  27. ^ a b Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA (August 2000). "Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity". J. Biol. Chem. 275 (31): 23500–8. doi:10.1074/jbc.M001557200. hdl:10026.1/10318. PMID 10825162.
  28. ^ Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA (October 2002). "Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases". J. Biol. Chem. 277 (43): 41110–9. doi:10.1074/jbc.M205396200. PMID 12181313.
  29. ^ Moens PB, Kolas NK, Tarsounas M, Marcon E, Cohen PE, Spyropoulos B (April 2002). "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. 115 (Pt 8): 1611–22. doi:10.1242/jcs.115.8.1611. PMID 11950880.
  30. ^ Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID (March 2000). "The Bloom's syndrome gene product interacts with topoisomerase III". J. Biol. Chem. 275 (13): 9636–44. doi:10.1074/jbc.275.13.9636. PMID 10734115.
  31. ^ Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA (June 2001). "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Hum. Mol. Genet. 10 (12): 1287–98. doi:10.1093/hmg/10.12.1287. PMID 11406610.
  32. ^ von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM, Hickson ID, Bohr VA (June 2002). "Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins". J. Biol. Chem. 277 (24): 22035–44. doi:10.1074/jbc.M200914200. PMID 11919194.

Further reading

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