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NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cellsHypomorphic mutations which lead to decreased function of the NBS1 gene are responsible for Nijmegen breakage syndrome, a rare autosomal recessive hereditary disorder that imparts an increased predisposition to development of malignancy. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex that plays a critical role in cellular responses to DNA damage and the maintenance of chromosomal integrity. Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1. Both TK6 and WTK1 cells showed an increased level of ionizing radiation-induced mutation at the TK and HPRT loci, impaired phosphorylation of H2AX (gamma-H2AX), and impaired activation of the cell cycle checkpoint regulating kinase, Chk2. In TK6 cells, ionizing radiation-induced accumulation of p53/p21 and apoptosis were reduced. There was a differential response to ionizing radiation-induced cell killing between TK6 and WTK1 cells after NBS1 knockdown; TK6 cells were more resistant to killing, whereas WTK1 cells were more sensitive. NBS1 deficiency also resulted in a significant increase in telomere association that was independent of radiation exposure and p53 status. Our results provide the first experimental evidence that NBS1 deficiency in human cells leads to hypermutability and telomere associations, phenotypes that may contribute to the cancer predisposition seen among patients with this disease.
Document ID
20050218649
Acquisition Source
Johnson Space Center
Document Type
Reprint (Version printed in journal)
Authors
Zhang, Ying
(Colorado State University Fort Collins, Colorado 80523, United States)
Lim, Chang U K.
Williams, Eli S.
Zhou, Junqing
Zhang, Qinming
Fox, Michael H.
Bailey, Susan M.
Liber, Howard L.
Date Acquired
August 23, 2013
Publication Date
July 1, 2005
Publication Information
Publication: Cancer research
Volume: 65
Issue: 13
ISSN: 0008-5472
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: CA49696
CONTRACT_GRANT: NAG9-1516
CONTRACT_GRANT: NAG9-1516
Distribution Limits
Public
Copyright
Other
Keywords
Non-NASA Center
NASA Discipline Radiation Health

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