The Human Bloom Syndrome Gene Suppresses the DNA Replication and Repair Defects of Yeast Dna2 Mutants

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Jun 27

PMID 12826610

Citations 45

Authors

Osamu Imamura

Judith L Campbell

Affiliations

Soon will be listed here.

Abstract

Bloom syndrome is a disorder of profound and early cancer predisposition in which cells become hypermutable, exhibit high frequency of sister chromatid exchanges, and show increased micronuclei. BLM, the gene mutated in Bloom syndrome, has been cloned previously, and the BLM protein is a member of the RecQ family of DNA helicases. Many lines of evidence suggest that BLM is involved either directly in DNA replication or in surveillance during DNA replication, but its specific roles remain unknown. Here we show that hBLM can suppress both the temperature-sensitive growth defect and the DNA damage sensitivity of the yeast DNA replication mutant dna2-1. The dna2-1 mutant is defective in a helicase-nuclease that is required either to coordinate with the crucial Saccharomyces cerevisiae (sc) FEN1 nuclease in Okazaki fragment maturation or to compensate for scFEN1 when its activity is impaired. We show that human BLM interacts with both scDna2 and scFEN1 by using coimmunoprecipitation from yeast extracts, suggesting that human BLM participates in the same steps of DNA replication or repair as scFEN1 and scDna2.

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References

Jin Y, Ayyagari R, Resnick M, Gordenin D, Burgers P . Okazaki fragment maturation in yeast. II. Cooperation between the polymerase and 3'-5'-exonuclease activities of Pol delta in the creation of a ligatable nick. J Biol Chem. 2002; 278(3):1626-33. DOI: 10.1074/jbc.M209803200. View

Watt P, Louis E, Borts R, Hickson I . Sgs1: a eukaryotic homolog of E. coli RecQ that interacts with topoisomerase II in vivo and is required for faithful chromosome segregation. Cell. 1995; 81(2):253-60. DOI: 10.1016/0092-8674(95)90335-6. View

Sengupta S, Linke S, Pedeux R, Yang Q, Farnsworth J, Garfield S . BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. EMBO J. 2003; 22(5):1210-22. PMC: 150347. DOI: 10.1093/emboj/cdg114. View

Huber M, Lee D, Maizels N . G4 DNA unwinding by BLM and Sgs1p: substrate specificity and substrate-specific inhibition. Nucleic Acids Res. 2002; 30(18):3954-61. PMC: 137114. DOI: 10.1093/nar/gkf530. View

Weitao T, Budd M, Mays Hoopes L, Campbell J . Dna2 helicase/nuclease causes replicative fork stalling and double-strand breaks in the ribosomal DNA of Saccharomyces cerevisiae. J Biol Chem. 2003; 278(25):22513-22. DOI: 10.1074/jbc.M301610200. View

Cohen H, Sinclair D . Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase. Proc Natl Acad Sci U S A. 2001; 98(6):3174-9. PMC: 30626. DOI: 10.1073/pnas.061579598. View

Stavropoulos D, Bradshaw P, Li X, Pasic I, Truong K, Ikura M . The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum Mol Genet. 2002; 11(25):3135-44. DOI: 10.1093/hmg/11.25.3135. View

Sun H, Karow J, Hickson I, Maizels N . The Bloom's syndrome helicase unwinds G4 DNA. J Biol Chem. 1998; 273(42):27587-92. DOI: 10.1074/jbc.273.42.27587. View

Kitao S, Ohsugi I, Ichikawa K, Goto M, Furuichi Y, Shimamoto A . Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Genomics. 1999; 54(3):443-52. DOI: 10.1006/geno.1998.5595. View

10.

Bae S, Bae K, Kim J, Seo Y . RPA governs endonuclease switching during processing of Okazaki fragments in eukaryotes. Nature. 2001; 412(6845):456-61. DOI: 10.1038/35086609. View

11.

Frei C, Gasser S . The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication checkpoint and colocalizes with Rad53p in S-phase-specific foci. Genes Dev. 2000; 14(1):81-96. PMC: 316339. View

12.

Waga S, Stillman B . Anatomy of a DNA replication fork revealed by reconstitution of SV40 DNA replication in vitro. Nature. 1994; 369(6477):207-12. DOI: 10.1038/369207a0. View

13.

Braguglia D, Heun P, Pasero P, Duncker B, Gasser S . Semi-conservative replication in yeast nuclear extracts requires Dna2 helicase and supercoiled template. J Mol Biol. 1998; 281(4):631-49. DOI: 10.1006/jmbi.1998.1973. View

14.

Choe W, Budd M, Imamura O, Hoopes L, Campbell J . Dynamic localization of an Okazaki fragment processing protein suggests a novel role in telomere replication. Mol Cell Biol. 2002; 22(12):4202-17. PMC: 133873. DOI: 10.1128/MCB.22.12.4202-4217.2002. View

15.

Ireland M, Reinke S, Livingston D . The impact of lagging strand replication mutations on the stability of CAG repeat tracts in yeast. Genetics. 2000; 155(4):1657-65. PMC: 1461208. DOI: 10.1093/genetics/155.4.1657. View

16.

Budd M, Campbell J . The pattern of sensitivity of yeast dna2 mutants to DNA damaging agents suggests a role in DSB and postreplication repair pathways. Mutat Res. 2000; 459(3):173-86. DOI: 10.1016/s0921-8777(99)00072-5. View

17.

Budd M, Campbell J . A yeast gene required for DNA replication encodes a protein with homology to DNA helicases. Proc Natl Acad Sci U S A. 1995; 92(17):7642-6. PMC: 41201. DOI: 10.1073/pnas.92.17.7642. View

18.

Myung K, Datta A, Kolodner R . Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae. Cell. 2001; 104(3):397-408. DOI: 10.1016/s0092-8674(01)00227-6. View

19.

Hickson I, Davies S, Li J, Levitt N, Mohaghegh P, North P . Role of the Bloom's syndrome helicase in maintenance of genome stability. Biochem Soc Trans. 2001; 29(Pt 2):201-4. DOI: 10.1042/0300-5127:0290201. View

20.

Hand R, German J . A retarded rate of DNA chain growth in Bloom's syndrome. Proc Natl Acad Sci U S A. 1975; 72(2):758-62. PMC: 432396. DOI: 10.1073/pnas.72.2.758. View