Bloom syndrome protein explained

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

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.

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. 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 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.^[6] 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.^[6]

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.^[7] 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^[7]

Interactions

Bloom syndrome protein has been shown to interact with:

• ATM,^{[8] [9]}
• CHAF1A,^[10]
• CHEK1,^[11]
• FANCM,^[12]
• FEN1,^[13]
• H2AFX,^[11]
• MCM6^[14]
• MLH1^{[8] [15] [16]}
• P53,^{[11] [17] [18] [19]}
• RAD51L3,^[20]
• RAD51,^[21]
• RPA1,^{[22] [23] [24]}
• TOP3A,^{[25] [22] [26] [27]}
• TP53BP1,^[11]
• WRN,^[28] and
• XRCC2.^[20]

Further reading

• Woo LL, Onel K, Ellis NA . The broken genome: genetic and pharmacologic approaches to breaking DNA . Ann. Med. . 39 . 3 . 208–18 . 2007 . 17457718 . 10.1080/08035250601167136 . 30395226 . free .
• 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. . 89 . 17 . 7968–72 . 1992 . 1518822 . 49836 . 10.1073/pnas.89.17.7968 . 1992PNAS...89.7968M . free .
• 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 . 83 . 4 . 655–66 . 1995 . 7585968 . 10.1016/0092-8674(95)90105-1 . 13439128 . free .
• 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. . 91 . 14 . 6669–73 . 1994 . 8022833 . 44264 . 10.1073/pnas.91.14.6669 . 1994PNAS...91.6669G . free .
• 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. . 6 . 9 . 1427–34 . 1998 . 9285778 . 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. . 240 . 2 . 348–53 . 1997 . 9388480 . 10.1006/bbrc.1997.7648 .
• Yankiwski V, Marciniak RA, Guarente L, Neff NF . Nuclear structure in normal and Bloom syndrome cells . Proc. Natl. Acad. Sci. U.S.A. . 97 . 10 . 5214–9 . 2000 . 10779560 . 25808 . 10.1073/pnas.090525897 . 2000PNAS...97.5214Y . free .
• 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. . 97 . 12 . 6504–8 . 2000 . 10823897 . 18638 . 10.1073/pnas.100448097 . 2000PNAS...97.6504K . free .
• 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 . 19 . 23 . 2731–8 . 2000 . 10851073 . 10.1038/sj.onc.1203595 . 13089263 .
• 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. . 15 . 6 . 584–5 . 2000 . 10862105 . 10.1002/1098-1004(200006)15:6<584::AID-HUMU28>3.0.CO;2-I . 41245824 . free .
• 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. . 28 . 12 . 2420–30 . 2000 . 10871376 . 102731 . 10.1093/nar/28.12.2420 .
• Book: Langer K, Cunniff CM, Kucine N . Bloom Syndrome . University of Washington, Seattle . GeneReviews® [Internet] . October 2023 . 20301572 . NBK1398 .

Notes and References

1. Karow JK, Chakraverty RK, Hickson ID . The Bloom's syndrome gene product is a 3'-5' DNA helicase . J Biol Chem . 272 . 49 . 30611–4 . January 1998 . 9388193 . 10.1074/jbc.272.49.30611 . free .
2. Web site: Bloom syndrome. Genetics Home Reference. NIH. 19 March 2013.
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 . 46 . 1 . 43–53 . 2012 . 22500736 . 3328772 . 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. . 112 . 15 . 4713–8 . 2015 . 25825745 . 4403193 . 10.1073/pnas.1423107112 . 1854/LU-6829814 . 2015PNAS..112.4713S . free .
5. Crismani W, Girard C, Froger N, Pradillo M, Santos JL, Chelysheva L, Copenhaver GP, Horlow C, Mercier R . 14570996 . FANCM limits meiotic crossovers . Science . 336 . 6088 . 1588–90 . 2012 . 22723424 . 10.1126/science.1220381 . 2012Sci...336.1588C .
6. 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 . 162 . 7 . 1197–209 . September 2003 . 14517203 . 2173967 . 10.1083/jcb.200304016 .
7. 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 . 511 . 2 . 145–78 . June 2002 . 12052432 . 10.1016/s1383-5742(02)00009-1 .
8. 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. . 14 . 8 . 927–39 . April 2000 . 10783165 . 316544 . 10.1101/gad.14.8.927.
9. 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. . 277 . 34 . 30515–23 . August 2002 . 12034743 . 10.1074/jbc.M203801200 . free .
10. 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. . 24 . 11 . 4710–9 . June 2004 . 15143166 . 416397 . 10.1128/MCB.24.11.4710-4719.2004 .
11. 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. . 166 . 6 . 801–13 . September 2004 . 15364958 . 2172115 . 10.1083/jcb.200405128 .
12. Deans AJ, West SC . FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia . Mol. Cell . 36 . 6 . 943–53 . 24 December 2009 . 20064461 . 10.1016/j.molcel.2009.12.006 . free .
13. 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. . 279 . 11 . 9847–56 . March 2004 . 14688284 . 10.1074/jbc.M309898200 . free .
14. Shastri . Vivek . Subramanian . Veena . A novel cell-cycle-regulated interaction of the Bloom syndrome helicase BLM with Mcm6 controls replication-linked processes . Nucleic Acids Research . 7 September 2021 . 49 . 15 . 8699–8713 . 10.1093/nar/gkab663 . 34370039 . 8421143 . free .
15. 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. . 276 . 32 . 30031–5 . August 2001 . 11325959 . 10.1074/jbc.M009664200 . free.
16. 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. . 29 . 21 . 4378–86 . November 2001 . 11691925 . 60193 . 10.1093/nar/29.21.4378.
17. 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. . 276 . 35 . 32948–55 . August 2001 . 11399766 . 10.1074/jbc.M103298200 . free .
18. 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 . 20 . 57 . 8276–80 . December 2001 . 11781842 . 10.1038/sj.onc.1205120 . 13084911 .
19. 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. . 277 . 35 . 31980–7 . August 2002 . 12080066 . 10.1074/jbc.M204111200 . free . 10026.1/10341 . free .
20. 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. . 278 . 48 . 48357–66 . November 2003 . 12975363 . 10.1074/jbc.M308838200 . 10026.1/10297 . free . free .
21. 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. . 276 . 22 . 19375–81 . June 2001 . 11278509 . 10.1074/jbc.M009471200 . free .
22. 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. . 275 . 31 . 23500–8 . August 2000 . 10825162 . 10.1074/jbc.M001557200 . free . 10026.1/10318 . free .
23. 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. . 277 . 43 . 41110–9 . October 2002 . 12181313 . 10.1074/jbc.M205396200 . free .
24. 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. . 115 . Pt 8 . 1611–22 . April 2002 . 10.1242/jcs.115.8.1611 . 11950880 .
25. 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. . 29 . 15 . 3172–80 . August 2001 . 11470874 . 55826 . 10.1093/nar/29.15.3172.
26. 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. . 275 . 13 . 9636–44 . March 2000 . 10734115 . 10.1074/jbc.275.13.9636. free .
27. 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. . 10 . 12 . 1287–98 . June 2001 . 11406610 . 10.1093/hmg/10.12.1287. free .
28. 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. . 277 . 24 . 22035–44 . June 2002 . 11919194 . 10.1074/jbc.M200914200 . free .