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Human MRE11 is inactivated in mismatch repair-deficient cancers
Giuseppe Giannini1, Elisabetta Ristori, Fabio Cerignoli
1Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Rome, Italy. giuseppe.giannini@uniroma1.it
Abstract:
Mutations of the ATM and NBS1 genes are responsible for the inherited Ataxia-Telangiectasia and Nijmegen Breakage Syndrome, both of which are associated with a predisposition to cancer. A related syndrome, the Ataxia-Telangiectasia-like disorder, is due to mutations of the MRE11 gene. However, the role of this gene in cancer development has not been established. Here we describe an often homozygous mutation of the poly(T)11 repeat within human MRE11 intron 4 that leads to aberrant splicing, impairment of wild-type MRE11 expression and generation of a truncated protein. This mutation is present in mismatch repair-deficient, but not proficient, colorectal cancer cell lines and primary tumours and is associated with reduced expression of the MRE11--NBS1--RAD50 complex, an impaired S-phase checkpoint and abrogation of MRE11 and NBS1 ionizing radiation-induced nuclear foci. Our findings identify MRE11 as a novel and major target for inactivation in mismatch repair-defective cells and suggest its impairment may contribute to the development of colorectal cancer.
Insights
A common MRE11 gene mutation causes abnormal splicing, leading to a truncated protein. This MRE11 gene defect is found in mismatch repair-deficient colorectal cancers, suggesting its role in cancer development.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Ataxia-Telangiectasia (AT) and Nijmegen Breakage Syndrome (NBS) are inherited disorders linked to cancer predisposition, caused by ATM and NBS1 gene mutations.
- Ataxia-Telangiectasia-like disorder is associated with MRE11 gene mutations, but its role in cancer remains unclear.
Purpose of the Study:
- To investigate the role of the MRE11 gene in colorectal cancer development.
- To identify specific MRE11 mutations and their functional consequences in cancer cells.
Main Methods:
- Analysis of MRE11 gene mutations, specifically the poly(T)11 repeat in intron 4.
- Assessment of gene splicing, protein expression, and DNA repair complex formation (MRE11-NBS1-RAD50).
- Evaluation of cell cycle checkpoints and ionizing radiation-induced nuclear foci in cancer cell lines and primary tumors.
Main Results:
- A homozygous mutation in the MRE11 intron 4 poly(T)11 repeat was identified, causing aberrant splicing and a truncated MRE11 protein.
- This mutation was found in mismatch repair-deficient (MMR-D) colorectal cancer cell lines and tumors, but not in mismatch repair-proficient (MMR-P) ones.
- The mutation correlated with reduced MRE11-NBS1-RAD50 complex expression, impaired S-phase checkpoint, and abrogated MRE11/NBS1 foci formation after ionizing radiation.
Conclusions:
- MRE11 is a novel and significant target for inactivation in MMR-D colorectal cancers.
- MRE11 impairment, due to this specific mutation, may contribute to the pathogenesis of colorectal cancer.