Dataset Information

Mre11-Rad50-Nbs complex is required to cap telomeres during Drosophila embryogenesis.

ABSTRACT: Using Drosophila as a model system, we identified here a stringent requirement for Mre11-Rad50-Nbs (MRN) function in telomere protection during early embryonic development. Animals homozygous for hypomorphic mutations in either mre11 or nbs develop normally with minimal telomere dysfunction. However, they produce inviable embryos that succumb to failure of mitosis caused by covalent fusion of telomeric DNA. Interestingly, the molecular defect is not the absence of MRN interaction or of Mre11 nuclease activities, but the depletion of the maternal pool of Nbs protein in these embryos. Because of Nbs depletion, Mre11 and Rad50 (MR) are excluded from chromatin. This maternal effect lethality in Drosophila is similar to that seen in mice carrying hypomorphic mrn mutations found in human patients, suggesting a common defect in telomere maintenance because of the loss of MRN integrity.

SUBMITTER: Gao G

PROVIDER: S-EPMC2705596 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Mre11-Rad50-Nbs complex is required to cap telomeres during Drosophila embryogenesis.

Gao Guanjun G Bi Xiaolin X Chen Jie J Srikanta Deepa D Rong Yikang S YS

Proceedings of the National Academy of Sciences of the United States of America 20090611 26

Using Drosophila as a model system, we identified here a stringent requirement for Mre11-Rad50-Nbs (MRN) function in telomere protection during early embryonic development. Animals homozygous for hypomorphic mutations in either mre11 or nbs develop normally with minimal telomere dysfunction. However, they produce inviable embryos that succumb to failure of mitosis caused by covalent fusion of telomeric DNA. Interestingly, the molecular defect is not the absence of MRN interaction or of Mre11 nuc ...[more]

PMID: 19520832

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Project description:BackgroundThe MRE11, RAD50, and NBN genes encode proteins of the MRE11-RAD50-NBN (MRN) complex involved in cellular response to DNA damage and the maintenance of genome stability. In our previous study we showed that the germline p.I171V mutation in NBN may be considered as a risk factor in the development of childhood acute lymphoblastic leukemia (ALL) and some specific haplotypes of that gene may be associated with childhood leukemia. These findings raise important questions about the role of mutations in others genes of the MRN complex in childhood leukemia. The aim of this study was to answer the question whether MRE11 and RAD50 alterations may be associated with childhood ALL or AML.MethodsWe estimated the frequency of constitutional mutations and polymorphisms in selected regions of MRE11, RAD50, and NBN in the group of 220 children diagnosed with childhood leukemias and controls (n=504/2200). The analysis was performed by specific amplification of region of interest by PCR and followed by multi-temperature single-strand conformation polymorphism (PCR-MSSCP) technique. We performed two molecular tests to examine any potential function of the detected the c.551+19G>A SNP in RAD50 gene. To our knowledge, this is the first analysis of the MRE11, RAD50 and NBN genes in childhood leukemia.ResultsThe frequency of either the AA genotype or A allele of RAD50_rs17166050 were significantly different in controls compared to leukemia group (ALL+AML) (p<0.0019 and p<0.0019, respectively). The cDNA analysis of AA or GA genotypes carriers has not revealed evidence of splicing abnormality of RAD50 pre-mRNA. We measured the allelic-specific expression of G and A alleles at c.551+19G>A and the statistically significant overexpression of the G allele has been observed. Additionally we confirmed the higher incidence of the p.I171V mutation in the leukemia group (7/220) than among controls (12/2400) (p<0.0001).ConclusionThe formerly reported sequence variants in the RAD50 and MRE11 gene may not constitute a risk factor of childhood ALL in Polish population. The RAD50_rs17166050 variant allele is linked to decreased ALL risk (p<0.0009, OR=0.6358 (95%CI: 0.4854-0.8327)). Despite the fact that there is no splicing abnormality in carriers of the variant allele but an excess of the G over the A allele was consistently observed. This data demonstrate that some specific alternations of the RAD50 gene may be associated with childhood ALL.

Dataset Information

Mre11-Rad50-Nbs complex is required to cap telomeres during Drosophila embryogenesis.

Publications

Mre11-Rad50-Nbs complex is required to cap telomeres during Drosophila embryogenesis.

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