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Effect of an MCM4 mutation that causes tumours in mouse on human MCM4/6/7 complex formation
Emi Watanabe1, Rie Ohara, Yukio Ishimi
1College of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 351-8511, Japan.
Abstract:
It has been reported that a point mutation of minichromosome maintenance (MCM)4 causes mammary carcinoma, and it deregulates DNA replication to produce abnormal chromosome structures. To understand the effect of this mutation at level of MCM2-7 interaction, we examined the effect of the same mutation of human MCM4 on the complex formation with MCM6 and MCM7 in insect cells. Human MCM4/6/7 complexes containing the mutated MCM4 were formed, but the hexameric complex formation was not evident in comparison with those containing wild-type MCM4. In binary expression of MCM4 and MCM6, decreased levels of MCM6 were recovered with the mutated MCM4, compared with wild-type MCM4. These results suggest that this mutation of MCM4 perturbs proper interaction with MCM6 to affect complex formation of MCM4/6/7 that is a core structure of MCM2-7 complex. Consistent with this notion, nuclear localization and MCM complex formation of forcedly expressed MCM4 in human cells are affected by this mutation. Thus, the defect of this mutant MCM4 in interacting with MCM6 may generate a decreased level of chromatin binding of MCM2-7 complex.
Insights
A mutation in minichromosome maintenance (MCM)4 disrupts MCM4/6/7 complex formation and nuclear localization. This defect in MCM4 interaction with MCM6 may reduce MCM2-7 complex binding to chromatin.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- A point mutation in minichromosome maintenance (MCM)4 is linked to mammary carcinoma and deregulation of DNA replication.
- Understanding the MCM2-7 complex's role in DNA replication and its structural integrity is crucial.
Purpose of the Study:
- To investigate the impact of a specific MCM4 mutation on the formation and function of the MCM4/6/7 complex.
- To elucidate how this mutation affects MCM2-7 complex assembly, nuclear localization, and chromatin binding.
Main Methods:
- Utilized insect cells for examining human MCM4/6/7 complex formation with wild-type and mutated MCM4.
- Performed binary expression studies of MCM4 and MCM6 to assess interaction levels.
- Analyzed nuclear localization and MCM complex formation of expressed MCM4 in human cells.
Main Results:
- Human MCM4/6/7 complexes formed with mutated MCM4, but hexameric complex formation was less evident compared to wild-type.
- Mutated MCM4 partially restored decreased MCM6 levels in binary expression, suggesting altered MCM4-MCM6 interaction.
- Nuclear localization and MCM complex formation of mutated MCM4 in human cells were impaired.
Conclusions:
- The MCM4 mutation perturbs the proper interaction with MCM6, affecting MCM4/6/7 complex assembly.
- This defect in MCM4-MCM6 interaction may lead to reduced chromatin binding of the MCM2-7 complex.
- The findings suggest a mechanism by which MCM4 mutations contribute to genomic instability and potentially cancer development.
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