Scientists at the City of Hope Cancer Center have uncovered evidence that abnormal DNA structures may be responsible for one of the earliest detectable chemical changes associated with the development of cancer.
The finding provides new insight into the formation of cancer and suggests new avenues of research into early detection and, possibly, treatment of the disease. The research is published in the January 9, 1998, issue of the Journal of Molecular Biology.
Scientists have known for some time that abnormal DNA structures called “hairpins” or “loops” can result from errors during the replication of DNA.
“The DNA molecule normally has the same double-helical shape regardless of the genetic information it encodes. The abnormal DNA structures we have been studying are like knots, hairpins, or loops—parts of the DNA molecule actually fold back on themselves,” says Steven Smith, phd, director of the Department of Cell and Tumor Biology at City of Hope Cancer Center.
Abnormal Structures Implicated in Cancer and Noncancerous Diseases
City of Hope scientists and other research groups have previously shown that these abnormal DNA structures can occur in oncogenes and other genes implicated in cancer, such as the retinoblastoma tumor-suppressor gene. In addition, these structures have been shown to occur in genes involved in noncancerous diseases.
“When we look at the molecular changes that occur at the level of DNA, we find the same molecular processes are at work in cancer, fragile X syndrome and Huntington’s chorea,” says Dr. Smith.
Usually, these abnormal structures are removed by the cell’s own repair mechanisms. However, when these repair mechanisms fail, the abnormal structures persist, eventually contributing to mutation and the development of cancer.
Abnormal Structures Affect Methylation
Dr. Smith and his coinvestigators found evidence that these abnormal DNA structures can account for one of the earliest detectable chemical changes in malignant cells—alterations in the pattern by which methyl groups are attached to the DNA molecule.
Normally, methyl groups are attached to DNA at many places throughout the genome. However, in the early stages of cancer, the pattern of methylation changes: the entire genome becomes undermethylated, while methyl groups become more concentrated at certain “hot spots.”
“Disturbance in methylation patterns is one of the earliest detectable events that occurs in a cancer cell and it has also been observed in certain neurological and retroviral diseases. Our research has enabled us to understand these important events in molecular terms,” says Dr. Smith, who is also director of the City of Hope Program in Molecular Carcinogenesis.
Stalled Enzymes
The new research suggests that abnormal DNA structures affect methylation by acting on the enzyme responsible for attaching methyl groups to the DNA. Methyltransferase normally interacts quickly with DNA in a rapid cycle of events that results in methylation of DNA and release of the enzyme. The City of Hope group has found, however, that when the enzyme encounters the hairpins and loops of abnormal DNA structures, it cannot complete this cycle of molecular events; instead, methyltransferase “stalls” midway through its cycle and is unable to move to other parts of the DNA molecule.
The investigators propose that the binding of the enzyme to the abnormal DNA structures accounts for the known alterations in methylation patterns in malignant cells, increasing the concentration of methyl groups at the sites of these structures, while preventing methyltransferase from attaching methyl groups to other parts of the DNA molecule.
First Unifying Hypothesis
“It’s becoming increasingly clear that most of the changes in methylation are associated with these unusual DNA structures,” says Dr. Smith. “This work provides the first unifying hypothesis to explain the relationship between these seemingly contradictory changes in DNA methylation and the development of cancer. One now begins to ask questions about the direct involvement of the methyltransferase itself in these processes instead of looking only at the involvement of its product—DNA methylation patterns.
“Our explanation for why methylation is one of the earliest detectable changes in the development of cancer may stimulate research into the development of a methylation detection method that could diagnose cancer at it’s earliest stage, which could result in more effective treatment.”
Coinvestigators on the study include: Mark R. Kho, MD, City of Hope Cancer Center (present affiliation, Philippine General Hospital, Manila, Philippines); David J. Baker, BS, City of Hope Cancer Center; and Ali Laayoun, phD, City of Hope Cancer Center (present affiliation, bioMericux, Venissieux, France).
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