Another type of oncogene is the gene encoding telomerase, a reverse transcriptase that is required to synthesize the hexamer repeat TTAGGG, a component of telomeres at the ends of chromosomes. Telomerase is needed because, during normal semiconservative replication of DNA, DNA polymerase can only add nucleotides to the 3′ end of DNA and cannot complete the synthesis of a growing strand all the way to the very end of that strand on the chromosome arm; thus, in the absence of a specific mechanism to allow replication of telomeres, the end of each chromosome arm would shorten significantly with each and every cell division.
In human germline cells and embryonic cells, telomeres contain ~15 kb of the telomeric repeat. As cells differentiate, telomerase activity declines in somatic tis sues; as telomerase function is lost, telomeres shorten, with a loss of ~35 bp of telomeric repeat DNA with each cell division. After hundreds of cell divisions, the chromosome ends become damaged, leading cells to stop dividing and enter G0 of the cell cycle; the cells will ultimately undergo apoptosis and die.
In contrast, in highly proliferative cells of tissues such as bone marrow, telomerase expression persists, allowing self- renewal. Similarly, telomerase persistence is observed in many tumors, which permits tumor cells to proliferate indefinitely. In some cases, increased telomerase activity results from chromosome or gene mutations that directly up- regulate the telomerase gene; in others, telomerase may be only one of many genes whose expression is altered by a transforming oncogene, such as MYC. The extent of oncogenesis resulting from disorders of telomere biology is still being recognized, as evidenced by classic telomere syndromes in which telomere attrition is a characteristic associated with cancer, and in disorders in which there is alternative lengthening of telomeres.
