A team of researchers from Professor Taro Yamashita at Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences has reported that telomerase reverse transcriptase (hTERT) (*2) (Figure 1, left), which is believed to be involved in cancer development by extending chromosome ends called telomeres (*1), has been shown to be activated in different ways with Division of Cancer Stem Cell, National Cancer Center Research Institute, Tokai University School of Medicine, Tohoku University Graduate School of Medicine, and National Cancer Center Research Institute. Cancer cells accumulate genomic abnormalities (*3) that lead to cell death as they proliferate, and we found that hTERT eliminates these genomic abnormalities by synthesizing RNA (Fig. 1, right). In other words, the new function of hTERT was to repair the genome and promote the survival of cancer cells.
When the existence of hTERT was examined in various cancer cells, this mechanism was also confirmed in sarcoma (*4), where hTERT was thought to be absent. Furthermore, it became clear that inhibition of the new function of hTERT renders the cancer cells unsurvivable and causes their death. These results are expected to lead to the development of new cancer therapies targeting the genome repair function of hTERT.
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The results of this research were published in the British scientific journal Nature Cell Biology on May 28, 2024.
Figure 1: Mechanism for genome regulation by telomerase reverse transcriptase.
Left: Telomerase reverse transcriptase (hTERT) functions to maintain telomeres.
Right: New enzymatic activity (RNA synthesis) eliminates abnormal genomic structures that are harmful to cancer cells.
【Presentation Points】
- Telomerase reverse transcriptase (hTERT) is widely known to be involved in the development and progression of cancer. hTERT promotes tumorigenesis through a novel mechanism.
- Originally, hTERT was thought to be involved in oncogenesis by extending chromosome ends called telomeres. In this study, we found that hTERT eliminates genomic abnormalities that are harmful to cancer cells, thereby favoring cancer survival.
- A study of a large number of cancer types confirmed this function, even in sarcomas, where hTERT was previously thought to be absent.
- Inhibition of the new function of hTERT discovered in this study was also confirmed to kill cancer cells, and is expected to lead to the development of therapies targeting the new function of hTERT.
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*1: Telomere
A structure at the end of chromosomal DNA that functions to protect the ends of chromosomes. In mammals, it consists of a repeating sequence of TTAGGG bases and a protein. In normal cells, telomeres shorten slightly with each division, leading to arrest of cell division. Cancer cells, on the other hand, prevent telomere shortening through increased expression of telomerase, an enzyme that elongates telomeres, and through homologous recombination, in which adjacent telomere sequences are copied from one another.
*2:Telomerase reverse transcriptase (hTERT)
Telomerase is an enzyme that adds characteristic repeating sequences to the ends of chromosomal DNA called telomeres, and its expression is upregulated in many cancers, leading to immortalization of cancer cells. Telomerase reverse transcriptase (hTERT) is one of the major subunits of telomerase and shows activity to add TTAGGG to telomeres. Recently, new functions of hTERT that are not related to telomerase have been revealed, and the molecular mechanism of hTERT has been elucidated.
*3: Genomic aberration
A harmful change that occurs in genomic DNA, in which our genetic information is stored. Known examples include insertions, deletions, substitutions, and other mutations of the bases that make up genomic DNA, as well as copy number abnormalities, in which multiple copies of a specific DNA base are generated. Other examples include structural abnormalities in which the structure of normal double-stranded DNA is altered.
*4: Sarcoma
Malignant tumors arising from bones and soft tissues (muscle, fat, etc.) throughout the body. Typical examples include osteosarcoma, chondrosarcoma, liposarcoma, and leiomyosarcoma. The frequency of occurrence is less than 1% of all malignant tumors, making it a rare cancer.
Click here to see the press release【Japanese only】
Journal: Nature Cell Biology
Researcher's Information: Taro Yamashita
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