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PMID:24816114

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Citation

Swan, MK, Legris, V, Tanner, A, Reaper, PM, Vial, S, Bordas, R, Pollard, JR, Charlton, PA, Golec, JM and Bertrand, JA (2014) Structure of human Bloom's syndrome helicase in complex with ADP and duplex DNA. Acta Crystallogr. D Biol. Crystallogr. 70:1465-75

Abstract

Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10-15% of cancers, where inhibitors of BLM are expected to facilitate telomere shortening, leading to apoptosis or senescence. Here, the crystal structure of the human BLM helicase in complex with ADP and a 3'-overhang DNA duplex is reported. In addition to the helicase core, the BLM construct used for crystallization (residues 640-1298) includes the RecQ C-terminal (RQC) and the helicase and ribonuclease D C-terminal (HRDC) domains. Analysis of the structure provides detailed information on the interactions of the protein with DNA and helps to explain the mechanism coupling ATP hydrolysis and DNA unwinding. In addition, mapping of the missense mutations onto the structure provides insights into the molecular basis of Bloom's syndrome.

Links

PubMed Online version:10.1107/S139900471400501X

Keywords

Adenosine Diphosphate/metabolism; Bloom Syndrome/genetics; Catalytic Domain; Crystallography, X-Ray; Humans; Hydrolysis; Models, Molecular; Mutation; Nucleic Acid Heteroduplexes; Protein Conformation; RecQ Helicases/chemistry; RecQ Helicases/genetics; RecQ Helicases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BLM

enables

GO:0008094: ATP-dependent activity, acting on DNA

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BLM

enables

GO:0003678: DNA helicase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BLM

enables

GO:0008094: DNA-dependent ATPase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BLM

enables

GO:0003677: DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BLM

enables

GO:0005524: ATP binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BLM

enables

GO:0008270: zinc ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BLM

enables

GO:0004003: ATP-dependent DNA helicase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BLM

involved_in

GO:0032508: DNA duplex unwinding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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