Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue
AUTOR(ES)
Grand, Cory L.
FONTE
National Academy of Sciences
RESUMO
We have demonstrated that a parallel G-quadruplex structure in the c-MYC promoter functions as a transcriptional repressor element. Furthermore, a specific G-to-A mutation in this element results in destabilization of the G-quadruplex repressor element and an increase in basal transcriptional activity. To validate this model in an in vivo context, we have examined the sequence of this region in human colorectal tumors and the surrounding normal tissue. We have found that ≈30% of tumors contain one of two specific G-to-A mutations, not present in the surrounding normal tissue, that destabilize the parallel G-quadruplex, which would be expected to give rise to abnormally high expression of c-MYC in these cells. In contrast, G-quadruplex-disruptive mutations were absent in 20 colon adenomas, suggesting that these mutations occur late in tumorigenesis. We have also demonstrated that these same mutations are found in established colorectal cell lines. NM23-H2 levels are lower in cancer tissues and cell lines that harbor these mutations. In cells with repressed levels of NM23-H2, the mutated and destabilized G-quadruplex silencer element can be reinstated by the addition of G-quadruplex-stabilizing compounds, providing an opportunity for therapeutic intervention for patients carrying these mutations.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=395936Documentos Relacionados
- Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription
- Specific interactions of distamycin with G-quadruplex DNA
- Identification and Characterization of Nucleolin as a c-myc G-quadruplex-binding Protein*
- The c-myc Insulator Element and Matrix Attachment Regions Define the c-myc Chromosomal Domain
- A G-quadruplex Stabilizer Induces M-phase Cell Cycle Arrest*