Impairment of double-strand breaks repair and aberrant splicing of ATM and MRE11 in leukemia-lymphoma cell lines with microsatellite instability.
Mutations of DNA double-strand breaks (DSB) repair genes, ATM, MRE11, RAD50, NBS1 and ATR, are postulated to play a role in the development of gastrointestinal malignancies with an impaired mismatch repair (MMR) function. In the present study, mutations of these genes together with the presence of microsatellite instability (MSI) were examined in 50 leukemia-lymphoma cell lines. MSI was detected in 13 (26%) lines. Mutations of intronic mononucleotide repeats in ATM and MRE11 were found in nine and six lines, respectively, whereas mutations of mononucleotide repeats of RAD50 were found in only one line, and none were found in either NBS1 or ATR. Frequencies of ATM and MRE11 mutations were significantly higher in MSI-positive than MSI-negative lines. These mutations generated aberrant splicing in both genes. The intensity of the aberrant transcript of ATM (497del22) was stronger in five lines harboring mononucleotide mutations of 2 bp or more than in the lines without or with a 1-bp mutation. The intensity of the aberrant transcript of MRE11 (315del88) was stronger in four lines with mononucleotide mutations than in lines without. The expression levels of ATM and MRE11 transcripts in MSI-positive lines were significantly higher than those in MSI-negative lines. MSI-positive cell lines showed delay or abrogation of DSB repair. The present study suggests that impairment of the MMR system causes aberrant transcripts in the DSB repair genes ATM and MRE11. This might result in inactivation of the DSB repair system, thus inducing an acceleration of genome instability and accumulation of genetic damage.
Ham
Maria Francisca
MF
Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita-shi, Osaka 565-0871, Japan.
Takakuwa
Tetsuya
T
Luo
Wen-Juan
WJ
Liu
Angen
A
Horii
Akira
A
Aozasa
Katsuyuki
K
D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D020137:Base Pair Mismatch / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019457:Chromosome Breakage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics*; D000076228:MRE11 Homologue Protein; D018895:Microsatellite Repeats; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes