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PMID:24049074

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Citation

Jain, A, Bacolla, A, Del Mundo, IM, Zhao, J, Wang, G and Vasquez, KM (2013) DHX9 helicase is involved in preventing genomic instability induced by alternatively structured DNA in human cells. Nucleic Acids Res. 41:10345-57

Abstract

Sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures in the human genome have been implicated in stimulating genomic instability. Previously, we found that a naturally occurring intra-molecular triplex (H-DNA) caused genetic instability in mammals largely in the form of DNA double-strand breaks. Thus, it is of interest to determine the mechanism(s) involved in processing H-DNA. Recently, we demonstrated that human DHX9 helicase preferentially unwinds inter-molecular triplex DNA in vitro. Herein, we used a mutation-reporter system containing H-DNA to examine the relevance of DHX9 activity on naturally occurring H-DNA structures in human cells. We found that H-DNA significantly increased mutagenesis in small-interfering siRNA-treated, DHX9-depleted cells, affecting mostly deletions. Moreover, DHX9 associated with H-DNA in the context of supercoiled plasmids. To further investigate the role of DHX9 in the recognition/processing of H-DNA, we performed binding assays in vitro and chromatin immunoprecipitation assays in U2OS cells. DHX9 recognized H-DNA, as evidenced by its binding to the H-DNA structure and enrichment at the H-DNA region compared with a control region in human cells. These composite data implicate DHX9 in processing H-DNA structures in vivo and support its role in the overall maintenance of genomic stability at sites of alternatively structured DNA.

Links

PubMed PMC3905860 Online version:10.1093/nar/gkt804

Keywords

Cell Line, Tumor; DEAD-box RNA Helicases/metabolism; DEAD-box RNA Helicases/physiology; DNA/chemistry; DNA/metabolism; Genomic Instability; Humans; Mutation; Neoplasm Proteins/metabolism; Neoplasm Proteins/physiology; Nucleic Acid Conformation; Plasmids/genetics

Significance

Annotations

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

HUMAN:DHX9

enables

GO:1990518: single-stranded 3'-5' DNA helicase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX9

enables

GO:0045142: triplex DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX9

enables

GO:0031490: chromatin DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX9

enables

GO:1990518: single-stranded DNA-dependent ATP-dependent 3'-5' DNA helicase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX9

involved_in

GO:0045739: positive regulation of DNA repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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