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PMID:14701760

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Citation

Hunt, CR, Dix, DJ, Sharma, GG, Pandita, RK, Gupta, A, Funk, M and Pandita, TK (2004) Genomic instability and enhanced radiosensitivity in Hsp70.1- and Hsp70.3-deficient mice. Mol. Cell. Biol. 24:899-911

Abstract

Heat shock proteins (HSPs) are highly conserved among all organisms from prokaryotes to eukaryotes. In mice, the HSP genes Hsp70.1 and Hsp70.3 are induced by both endogenous and exogenous stressors, such as heat and toxicants. In order to determine whether such proteins specifically influence genomic instability, mice deficient for Hsp70.1 and Hsp70.3 (Hsp70.1/3(-/-) mice) were generated by gene targeting. Mouse embryonic fibroblasts (MEFs) prepared from Hsp70.1/3(-/-) mice did not synthesize Hsp70.1 or Hsp70.3 after heat-induced stress. While the Hsp70.1/3(-/-) mutant mice were fertile, their cells displayed genomic instability that was enhanced by heat treatment. Cells from Hsp70.1/3(-/-) mice also display a higher frequency of chromosome end-to-end associations than do control Hsp70.1/3(+/+) cells. To determine whether observed genomic instability was related to defective chromosome repair, Hsp70.1/3(-/-) and Hsp70.1/3(+/+) fibroblasts were treated with ionizing radiation (IR) alone or heat and IR. Exposure to IR led to more residual chromosome aberrations, radioresistant DNA synthesis (a hallmark of genomic instability), increased cell killing, and enhanced IR-induced oncogenic transformation in Hsp70.1/3(-/-) cells. Heat treatment prior to IR exposure enhanced cell killing, S-phase-specific chromosome damage, and the frequency of transformants in Hsp70.1/3(-/-) cells in comparison to Hsp70.1/3(+/+) cells. Both in vivo and in vitro studies demonstrate for the first time that Hsp70.1 and Hsp70.3 have an essential role in maintaining genomic stability under stress conditions.

Links

PubMed PMC343815

Keywords

Animals; Cell Line; Cell Survival/genetics; Cell Survival/physiology; Cell Survival/radiation effects; Cell Transformation, Neoplastic; Chromosome Aberrations; Colony-Forming Units Assay; DNA Repair; Female; Gene Expression; Gene Targeting; Genomic Instability; HSP70 Heat-Shock Proteins/deficiency; HSP70 Heat-Shock Proteins/genetics; Hot Temperature; Male; Mice; Mice, Knockout; RNA, Messenger/genetics; RNA, Messenger/metabolism; Radiation Tolerance/genetics; Radiation Tolerance/physiology; Spermatocytes/pathology; Telomere/genetics

Significance

Annotations

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

MOUSE:HS71A

acts_upstream_of_or_within

GO:0000723: telomere maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3028843

P

Seeded From UniProt

complete

MOUSE:HS71A

acts_upstream_of_or_within

GO:0006281: DNA repair

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3028843

P

Seeded From UniProt

complete

MOUSE:HS71A

acts_upstream_of_or_within

GO:0009408: response to heat

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3028843

P

Seeded From UniProt

complete

MOUSE:TERT

enables

GO:0003720: telomerase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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