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Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression
Asa Karlsson1, Debabrita Deb-Basu, Athena Cherry
1Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305-5151, USA.
Abstract:
DNA repair mechanisms are essential for the maintenance of genomic integrity. Disruption of gene products responsible for DNA repair can result in chromosomal damage. Improperly repaired chromosomal damage can result in the loss of chromosomes or the generation of chromosomal deletions or translocations, which can lead to tumorigenesis. The MYC protooncogene is a transcription factor whose overexpression is frequently associated with human neoplasia. MYC has not been previously implicated in a role in DNA repair. Here we report that the overexpression of MYC disrupts the repair of double-strand DNA breaks, resulting in a several-magnitude increase in chromosomal breaks and translocations. We found that MYC inhibited the repair of gamma irradiation DNA breaks in normal human cells and blocked the repair of a single double-strand break engineered to occur in an immortal cell line. By spectral karyotypic analysis, we found that MYC even within one cell division cycle resulted in a several-magnitude increase in the frequency of chromosomal breaks and translocations in normal human cells. Hence, MYC overexpression may be a previously undescribed example of a dominant mutator that may fuel tumorigenesis by inducing chromosomal damage.
Insights
Overexpression of MYC disrupts DNA repair, leading to increased chromosomal breaks and translocations. This suggests MYC acts as a dominant mutator, potentially driving cancer by causing genomic instability.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- DNA repair mechanisms are crucial for maintaining genomic integrity.
- Disruptions in DNA repair can lead to chromosomal abnormalities and tumorigenesis.
- The MYC protooncogene is often overexpressed in human cancers but its role in DNA repair was unknown.
Purpose of the Study:
- To investigate the role of MYC overexpression in DNA double-strand break repair.
- To determine if MYC influences chromosomal stability.
Main Methods:
- Studied the effect of MYC overexpression on DNA repair in normal human cells exposed to gamma irradiation.
- Assessed MYC's impact on the repair of engineered double-strand breaks in an immortal cell line.
- Utilized spectral karyotyping to analyze chromosomal damage.
Main Results:
- MYC overexpression significantly inhibited the repair of DNA double-strand breaks.
- Observed a several-magnitude increase in chromosomal breaks and translocations in MYC-overexpressing cells.
- MYC induced substantial chromosomal damage within a single cell division cycle.
Conclusions:
- MYC overexpression disrupts DNA double-strand break repair, leading to genomic instability.
- MYC may function as a dominant mutator, promoting tumorigenesis through induced chromosomal damage.
- This study implicates MYC in a novel mechanism contributing to cancer development.