Defective DNA Strand Break Repair Causes Chromosomal Instability and Accelerates Liver Carcinogenesis in Mice

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dc.contributor.authorTeoh, Narcissus
dc.contributor.authorDan, Yock Young
dc.contributor.authorSwisshelm, Karen
dc.contributor.authorLehman, Stacey
dc.contributor.authorWright, Jocelyn H.
dc.contributor.authorHaque, Jamil
dc.contributor.authorGu, Yansong
dc.contributor.authorFausto, Nelson
dc.date.accessioned2015-12-08T22:23:52Z
dc.date.issued2008
dc.date.updated2015-12-08T08:55:37Z
dc.description.abstractChromosomal instability is a characteristic feature of hepatocellular carcinoma (HCC) but its origin and role in liver carcinogenesis are undefined. We tested whether a defect in the nonhomologous end-joining (NHEJ) DNA repair gene Ku70 was associated with chromosomal abnormalities and enhanced liver carcinogenesis. Male Ku70 NHEJ-deficient (Ku70-/-), heterozygote (Ku70 +/-), and wild-type (WT) mice were injected with diethylnitrosamine (DEN), a liver carcinogen, at age 15 days. Animals were killed at 3, 6, and 9 months for assessment of tumorigenesis and hepatocellular proliferation. For karyotype analysis, primary liver tumor cell cultures were prepared from HCCs arising in Ku70 mice of all genotypes. Compared to WT littermates, Ku70-/- mice injected with DEN displayed accelerated HCC development. Ku70-/- HCCs harbored clonal increases in numerical and structural aberrations of chromosomes 4, 5, 7, 8, 10, 14, and 19, many of which recapitulated the spectrum of equivalent chromosomal abnormalities observed in human HCC. Ku70-/- HCCs showed high proliferative activity with increased cyclin D1 and proliferating cell nuclear antigen expression, Aurora A kinase activity, enhanced ataxia telangiectasia mutated kinase and ubiquitination, and loss of p53 via proteasomal degradation, features which closely resemble those of human HCC. Conclusion: These findings demonstrate that defects in the NHEJ DNA repair pathway may participate in the disruption of cell cycle checkpoints leading to chromosomal instability and accelerated development of HCC.
dc.identifier.issn0270-9139
dc.identifier.urihttp://hdl.handle.net/1885/33051
dc.publisherW B Saunders Co
dc.sourceHepatology
dc.subjectKeywords: ATR protein; aurora A kinase; cell nucleus antigen; cyclin D1; protein p53; actin; aurora kinase; carcinogen; diethylnitrosamine; DNA binding protein; histone; Ku antigen; Mdm2 protein, mouse; protein MDM2; protein serine threonine kinase; ubiquitin; anim
dc.titleDefective DNA Strand Break Repair Causes Chromosomal Instability and Accelerates Liver Carcinogenesis in Mice
dc.typeJournal article
local.bibliographicCitation.issue6
local.bibliographicCitation.lastpage2088
local.bibliographicCitation.startpage2078
local.contributor.affiliationTeoh, Narcissus, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationDan, Yock Young, National University of Singapore
local.contributor.affiliationSwisshelm, Karen, University of Washington
local.contributor.affiliationLehman, Stacey, University of Washington
local.contributor.affiliationWright, Jocelyn H., University of Washington
local.contributor.affiliationHaque, Jamil, University of Washington
local.contributor.affiliationGu, Yansong, University of Washington
local.contributor.affiliationFausto, Nelson, University of Washington
local.contributor.authoremailu4325419@anu.edu.au
local.contributor.authoruidTeoh, Narcissus, u4325419
local.description.embargo2037-12-31
local.description.notesImported from ARIES
local.identifier.absfor110307 - Gastroenterology and Hepatology
local.identifier.ariespublicationu4241283xPUB98
local.identifier.citationvolume47
local.identifier.doi10.1002/hep.22194
local.identifier.scopusID2-s2.0-46249134069
local.identifier.thomsonID000256391500034
local.identifier.uidSubmittedByu4241283
local.type.statusPublished Version

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