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Impaired nonhomologous end-joining in mismatch repair-deficient colon carcinomas

Authors
 Kwi H Koh  ;  Hyun J Kang  ;  Long S Li  ;  Nam-Gyun Kim  ;  Kwon T You  ;  Eungi Yang  ;  Hyunki Kim  ;  Hee J Kim  ;  Chae-Ok Yun  ;  Kyung-Sup Kim  ;  Hoguen Kim 
Citation
 LABORATORY INVESTIGATION, Vol.85(9) : 1130-1138, 2005 
Journal Title
LABORATORY INVESTIGATION
ISSN
 0023-6837 
Issue Date
2005
MeSH
Base Pair Mismatch* ; Base Sequence ; Cell Line, Tumor ; Colonic Neoplasms/genetics* ; DNA Primers ; DNA Repair* ; DNA Repair Enzymes/genetics ; DNA-Binding Proteins/genetics ; Humans ; Immunoprecipitation ; RNA Splicing ; RNA, Small Interfering/genetics ; Recombination, Genetic*
Keywords
16025146
Abstract
Frameshift mutations of coding mononucleotide repeat of the hRAD50 gene and formation of the mutant hMRE11 splicing variant are frequent events in tumors with mismatch repair (MMR) deficiency. Both the hRAD50 and hMRE11 proteins form a heterotrimer with the NBS1, and this heterotrimer is involved in the double strand DNA break repair by homologous recombination and nonhomologous end-joining (NHEJ). In order to clarify the role of hRAD50 and hMRE11 gene alterations in MMR-deficient tumors, we analyzed the expression of the hRAD50 and hMRE11 proteins and we evaluated NHEJ in the seven MMR-deficient and five MMR-proficient colon cancer cell lines. Frameshift mutations of the hRAD50 gene were found in five of seven MMR-deficient cell lines, and this was directly related to the decreased expression of hRAD50 mRNA and protein. The mutant hMRE11 splicing variant was found in all of the seven MMR-deficient cell lines, and this was related to the decreased hMRE11 expression in four of the seven MMR-deficient cell lines. MMR-deficient cell lines with decreased hRAD50 and hMRE11 expressions were more sensitive to gamma-irradiation, and these cell lines showed an impaired NHEJ. The impairment of NHEJ was induced after knockdown of hRAD50 and hMRE11 through small interference RNA. Our findings suggest that mutations of hRAD50 and hMRE11 genes in MMR-deficient tumors are related to the defects in NHEJ, and this may result in chromosomal changes during the progression of tumor.
Files in This Item:
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DOI
10.1038/labinvest.3700315
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hyun Ju(강현주)
Kim, Kyung Sup(김경섭) ORCID logo https://orcid.org/0000-0001-8483-8537
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Kim, Hogeun(김호근)
Kim, Hee Jin(김희진) ORCID logo https://orcid.org/0000-0002-1139-6261
You, Kwon Tae(유권태)
Yun, Chae Ok(윤채옥)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/150444
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