Researchers at Georgetown University School of Medicine and the National Institutes of Health have linked the mutation of a protein essential in DNA synthesis to abnormal chromosome numbers in several forms of cancer.
Previous studies have shown that instability of chromosomes, the grouped stretches of DNA found in cells, is an early event in the development of a wide range of cancers. This instability usually leads to aneuploidy, or an abnormal number of chromosomes in the cell. It is believed that the instability is caused by the mutation of genes responsible for regulating the DNA replication that occurs whenever a cell divides. This theory is in line with the defining characteristic of cancer – uncontrolled cell division that can damage normal cells.
In their study published this August in Science, the researchers focused on mutations in STAG2, a gene that codes a subunit of the protein cohesin. Cohesin is responsible for the cohesion of chromosomes after DNA replication, hence its name. In particular, cohesin binds sister chromatids, the two identical copies of DNA that result after it is replicated.
The gene is located on the X chromosome, one of the two chromosomes that determine sex. Females carry two identical copies, XX, and males carry two non-identical sex chromosomes, XY. In all females, one of the X chromosomes is "silent" or deactivated.
Without both X chromosomes active, a deleterious mutation to just one copy of a gene found on an X chromosome is enough to cause a problem, such as a mutation to STAG2. In males, there is only one X chromosome, and therefore only one copy of a gene such as STAG2.
Such mutations were originally found in three cancer cell lines, resulting in the gene being completely inactive. Additional screening by the team discovered similar silencing mutations in an additional ten cancer cell lines.
Subsequent investigations were done on tumor cells taken from patients suffering glioblastoma (the most common and aggressive form of brain cancer), melanoma (skin cancer) and Ewing's sarcoma (bone cancer). The researchers found that a significant fraction of these cancers completely lost the ability to express the STAG2 gene.
To determine the exact relationship between this lack of expression and cancer, the team first sought to determine if the STAG2 mutations caused the chromosome instability and aneuploidy characteristic of cancer. Using a technique called somatic cell gene targeting, they corrected the mutations in two types of glioblastoma cell lines. This resulted in a recovery of STAG2 protein levels.
Results showed that compared to STAG2 deficient cells, these recovered cells showed ‘virtually perfect' sister chromatid cohesion. Afterwards the gene was "knocked out," or completely removed from the chromosome, eliminating the levels of cohesin. Furthermore, the period of time between the start of DNA replication and its completion was longer than in normal cells, a trait characteristic of aneuploid cells. This shows a direct relationship between sister chromatid cohesion and STAG2 expression.
Other studies have shown that cohesin is necessary for the proper transcription of genes. Transcription, along with translation, makes up the Central Dogma of biology, and is the process by which DNA codes RNA, and then RNA is used to code for the synthesis of proteins. Results showed that STAG2 had no effect on whether cells were able to transcribe genes; in the absence and presence of the STAG2 protein, transcription occurred at similar levels.
From their results, the researchers concluded that STAG2 possibly acts as a "caretaker" gene to other genes responsible for tumor suppression and cancer regulation. Inactivation of these caretaker genes would result in chromosomal instability, which is a proven consequence of inactivation of already established caretaker genes.
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