Bloom syndrome protein
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| Location (UCSC) | Chr 15: 90.72 – 90.82 Mb | Chr 7: 80.1 – 80.18 Mb | |||||||
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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
Meiosis
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
Bloom syndrome protein facilitates DNA repair when cells are stressed by agents that cause DNA damages, 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 H2AX 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 Repair of DNA damages 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
Bloom syndrome protein has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000197299 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030528 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9388193.
- ^ "Bloom syndrome". Genetics Home Reference. NIH. Retrieved 19 March 2013.
- ^ PMID 22500736.
- ^ PMID 25825745.
- S2CID 14570996.
- ^ a b Davalos AR, Campisi J. Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks. J Cell Biol. 2003 Sep 29;162(7):1197-209. doi: 10.1083/jcb.200304016. PMID: 14517203; PMCID: PMC2173967
- ^ 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 Aug 31;276(35):32948-55. doi: 10.1074/jbc.M103298200. Epub 2001 Jun 8. PMID: 11399766
- ^ a b Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res. 2002 Jun;511(2):145-78. doi: 10.1016/s1383-5742(02)00009-1. PMID: 12052432
- ^ PMID 10783165.
- PMID 12034743.
- PMID 15143166.
- ^ PMID 15364958.
- PMID 20064461.
- PMID 14688284.
- PMID 34370039.
- ^ PMID 11470874.
- PMID 11325959.
- PMID 11691925.
- PMID 11399766.
- S2CID 13084911.
- PMID 12080066.
- ^ PMID 12975363.
- PMID 11278509.
- ^ PMID 10825162.
- PMID 12181313.
- PMID 11950880.
- PMID 10734115.
- PMID 11406610.
- PMID 11919194.
Further reading
- Woo LL, Onel K, Ellis NA (2007). "The broken genome: genetic and pharmacologic approaches to breaking DNA". Ann. Med. 39 (3): 208–18. S2CID 30395226.
- McDaniel LD, Schultz RA (1992). "Elevated sister chromatid exchange phenotype of Bloom syndrome cells is complemented by human chromosome 15". Proc. Natl. Acad. Sci. U.S.A. 89 (17): 7968–72. PMID 1518822.
- Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J (1995). "The Bloom's syndrome gene product is homologous to RecQ helicases". Cell. 83 (4): 655–66. S2CID 13439128.
- German J, Roe AM, Leppert MF, Ellis NA (1994). "Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1". Proc. Natl. Acad. Sci. U.S.A. 91 (14): 6669–73. PMID 8022833.
- Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, Amor-Guéret M (1998). "Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome". Hum. Mol. Genet. 6 (9): 1427–34. PMID 9285778.
- Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N (1997). "BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal". Biochem. Biophys. Res. Commun. 240 (2): 348–53. PMID 9388480.
- Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID (2000). "The Bloom's syndrome gene product interacts with topoisomerase III". J. Biol. Chem. 275 (13): 9636–44. PMID 10734115.
- Yankiwski V, Marciniak RA, Guarente L, Neff NF (2000). "Nuclear structure in normal and Bloom syndrome cells". Proc. Natl. Acad. Sci. U.S.A. 97 (10): 5214–9. PMID 10779560.
- Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (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. PMID 10783165.
- Karow JK, Constantinou A, Li JL, West SC, Hickson ID (2000). "The Bloom's syndrome gene product promotes branch migration of Holliday junctions". Proc. Natl. Acad. Sci. U.S.A. 97 (12): 6504–8. PMID 10823897.
- Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA (2000). "Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity". J. Biol. Chem. 275 (31): 23500–8. PMID 10825162.
- Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Guéret M (2000). "Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase". Oncogene. 19 (23): 2731–8. S2CID 13089263.
- Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda N, Benslimane A, Amor-Guéret M (2000). "Identification of a novel BLM missense mutation (2706T>C) in a Moroccan patient with Bloom's syndrome". Hum. Mutat. 15 (6): 584–5. S2CID 41245824.
- Brosh RM, Karow JK, White EJ, Shaw ND, Hickson ID, Bohr VA (2000). "Potent inhibition of Werner and Bloom helicases by DNA minor groove binding drugs". Nucleic Acids Res. 28 (12): 2420–30. PMID 10871376.
- Wu L, Davies SL, Levitt NC, Hickson ID (2001). "Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51". J. Biol. Chem. 276 (22): 19375–81. PMID 11278509.
- Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J (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. PMID 11325959.
- 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 (2001). "Functional interaction of p53 and BLM DNA helicase in apoptosis". J. Biol. Chem. 276 (35): 32948–55. PMID 11399766.
- Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA (2001). "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Hum. Mol. Genet. 10 (12): 1287–98. PMID 11406610.
- Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP (2001). "Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIα". Nucleic Acids Res. 29 (15): 3172–80. PMID 11470874.
External links
- GeneReviews/NCBI/NIH/UW entry on Bloom Syndrome
- Human BLM genome location and BLM gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P54132 (Bloom syndrome protein) at the PDBe-KB.
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