Biology:Bloom syndrome protein
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Short description: Mammalian protein found in humans
 Generic protein structure example |
Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.[1]
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.[2]
Meiosis
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.[3] 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.[3]
In the plant Arabidopsis thaliana, homologs of the Sgs1(BLM) helicase act as major barriers to meiotic CO formation.[4] 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.[5] Sequela-Arnaud et al.[4] 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.
Interactions
Bloom syndrome protein has been shown to interact with:
- ATM,[6][7]
- CHAF1A,[8]
- CHEK1,[9]
- FANCM,[10]
- FEN1,[11]
- H2AFX,[9]
- MCM6[12]
- MLH1[6][13][14][15]
- P53,[9][16][17][18]
- RAD51L3,[19]
- RAD51,[20]
- RPA1,[21][22][23]
- TOP3A,[13][21][24][25]
- TP53BP1,[9]
- WRN,[26] and
- XRCC2.[19]
References
- ↑ "The Bloom's syndrome gene product is a 3'-5' DNA helicase". J Biol Chem 272 (49): 30611–4. January 1998. doi:10.1074/jbc.272.49.30611. PMID 9388193.
- ↑ "Bloom syndrome". Genetics Home Reference. NIH. http://ghr.nlm.nih.gov/condition/bloom-syndrome.
- ↑ 3.0 3.1 "BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism". Mol. Cell 46 (1): 43–53. 2012. doi:10.1016/j.molcel.2012.02.020. PMID 22500736.
- ↑ 4.0 4.1 "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. 2015. doi:10.1073/pnas.1423107112. PMID 25825745. Bibcode: 2015PNAS..112.4713S.
- ↑ "FANCM limits meiotic crossovers". Science 336 (6088): 1588–90. 2012. doi:10.1126/science.1220381. PMID 22723424. Bibcode: 2012Sci...336.1588C.
- ↑ 6.0 6.1 "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. April 2000. doi:10.1101/gad.14.8.927. PMID 10783165.
- ↑ "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM". J. Biol. Chem. 277 (34): 30515–23. August 2002. doi:10.1074/jbc.M203801200. PMID 12034743.
- ↑ "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. June 2004. doi:10.1128/MCB.24.11.4710-4719.2004. PMID 15143166.
- ↑ 9.0 9.1 9.2 9.3 "Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest". J. Cell Biol. 166 (6): 801–13. September 2004. doi:10.1083/jcb.200405128. PMID 15364958.
- ↑ "FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia". Mol. Cell 36 (6): 943–53. 24 December 2009. doi:10.1016/j.molcel.2009.12.006. PMID 20064461.
- ↑ "Stimulation of flap endonuclease-1 by the Bloom's syndrome protein". J. Biol. Chem. 279 (11): 9847–56. March 2004. doi:10.1074/jbc.M309898200. PMID 14688284.
- ↑ 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. PMID 34370039.
- ↑ 13.0 13.1 "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. August 2001. doi:10.1093/nar/29.15.3172. PMID 11470874.
- ↑ "The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair". J. Biol. Chem. 276 (32): 30031–5. August 2001. doi:10.1074/jbc.M009664200. PMID 11325959.
- ↑ "Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1". Nucleic Acids Res. 29 (21): 4378–86. November 2001. doi:10.1093/nar/29.21.4378. PMID 11691925.
- ↑ "Functional interaction of p53 and BLM DNA helicase in apoptosis". J. Biol. Chem. 276 (35): 32948–55. August 2001. doi:10.1074/jbc.M103298200. PMID 11399766.
- ↑ "The Bloom syndrome protein interacts and cooperates with p53 in regulation of transcription and cell growth control". Oncogene 20 (57): 8276–80. December 2001. doi:10.1038/sj.onc.1205120. PMID 11781842.
- ↑ "The processing of Holliday junctions by BLM and WRN helicases is regulated by p53". J. Biol. Chem. 277 (35): 31980–7. August 2002. doi:10.1074/jbc.M204111200. PMID 12080066.
- ↑ 19.0 19.1 "Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D)". J. Biol. Chem. 278 (48): 48357–66. November 2003. doi:10.1074/jbc.M308838200. PMID 12975363.
- ↑ "Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51". J. Biol. Chem. 276 (22): 19375–81. June 2001. doi:10.1074/jbc.M009471200. PMID 11278509.
- ↑ 21.0 21.1 "Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity". J. Biol. Chem. 275 (31): 23500–8. August 2000. doi:10.1074/jbc.M001557200. PMID 10825162.
- ↑ "Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases". J. Biol. Chem. 277 (43): 41110–9. October 2002. doi:10.1074/jbc.M205396200. PMID 12181313.
- ↑ "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. April 2002. doi:10.1242/jcs.115.8.1611. PMID 11950880.
- ↑ "The Bloom's syndrome gene product interacts with topoisomerase III". J. Biol. Chem. 275 (13): 9636–44. March 2000. doi:10.1074/jbc.275.13.9636. PMID 10734115.
- ↑ "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Hum. Mol. Genet. 10 (12): 1287–98. June 2001. doi:10.1093/hmg/10.12.1287. PMID 11406610.
- ↑ "Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins". J. Biol. Chem. 277 (24): 22035–44. June 2002. doi:10.1074/jbc.M200914200. PMID 11919194.
Further reading
- "The broken genome: genetic and pharmacologic approaches to breaking DNA". Ann. Med. 39 (3): 208–18. 2007. doi:10.1080/08035250601167136. PMID 17457718.
- "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. 1992. doi:10.1073/pnas.89.17.7968. PMID 1518822. Bibcode: 1992PNAS...89.7968M.
- "The Bloom's syndrome gene product is homologous to RecQ helicases". Cell 83 (4): 655–66. 1995. doi:10.1016/0092-8674(95)90105-1. PMID 7585968.
- "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. 1994. doi:10.1073/pnas.91.14.6669. PMID 8022833. Bibcode: 1994PNAS...91.6669G.
- "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. 1998. doi:10.1093/hmg/6.9.1427. PMID 9285778.
- "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. 1997. doi:10.1006/bbrc.1997.7648. PMID 9388480.
- "The Bloom's syndrome gene product interacts with topoisomerase III". J. Biol. Chem. 275 (13): 9636–44. 2000. doi:10.1074/jbc.275.13.9636. PMID 10734115.
- "Nuclear structure in normal and Bloom syndrome cells". Proc. Natl. Acad. Sci. U.S.A. 97 (10): 5214–9. 2000. doi:10.1073/pnas.090525897. PMID 10779560. Bibcode: 2000PNAS...97.5214Y.
- "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. 2000. doi:10.1101/gad.14.8.927. PMID 10783165.
- "The Bloom's syndrome gene product promotes branch migration of Holliday junctions". Proc. Natl. Acad. Sci. U.S.A. 97 (12): 6504–8. 2000. doi:10.1073/pnas.100448097. PMID 10823897. Bibcode: 2000PNAS...97.6504K.
- "Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity". J. Biol. Chem. 275 (31): 23500–8. 2000. doi:10.1074/jbc.M001557200. PMID 10825162.
- "Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase". Oncogene 19 (23): 2731–8. 2000. doi:10.1038/sj.onc.1203595. PMID 10851073.
- "Identification of a novel BLM missense mutation (2706T>C) in a Moroccan patient with Bloom's syndrome". Hum. Mutat. 15 (6): 584–5. 2000. doi:10.1002/1098-1004(200006)15:6<584::AID-HUMU28>3.0.CO;2-I. PMID 10862105.
- "Potent inhibition of Werner and Bloom helicases by DNA minor groove binding drugs". Nucleic Acids Res. 28 (12): 2420–30. 2000. doi:10.1093/nar/28.12.2420. PMID 10871376.
- "Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51". J. Biol. Chem. 276 (22): 19375–81. 2001. doi:10.1074/jbc.M009471200. PMID 11278509.
- "The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair". J. Biol. Chem. 276 (32): 30031–5. 2001. doi:10.1074/jbc.M009664200. PMID 11325959.
- "Functional interaction of p53 and BLM DNA helicase in apoptosis". J. Biol. Chem. 276 (35): 32948–55. 2001. doi:10.1074/jbc.M103298200. PMID 11399766.
- "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Hum. Mol. Genet. 10 (12): 1287–98. 2001. doi:10.1093/hmg/10.12.1287. PMID 11406610.
- "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. 2001. doi:10.1093/nar/29.15.3172. 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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