Impaired nonhomologous end-joining in mismatch repair-deficient colon carcinomas View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2005-07-18

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

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 γ-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. More... »

PAGES

1130-1138

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/labinvest.3700315

DOI

http://dx.doi.org/10.1038/labinvest.3700315

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16025146


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71 knockdown
72 lines
73 mRNA
74 mismatch repair deficiency
75 mononucleotide repeats
76 mutations
77 order
78 progression
79 progression of tumors
80 protein
81 recombination
82 repair
83 repair deficiency
84 repeats
85 role
86 small interference RNA
87 splicing variants
88 strand DNA break repair
89 tumors
90 variants
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