The stability of telomere length and structure is closely related to carcinogenesis, and cancer cells gain the ability to live forever through telomere maintenance mechanisms. Telomere maintenance of cancer cells is mostly achieved through telomerase activation.
However, when telomerase is inactivated or insufficient, cancer cells also have another way to lengthen telomeres, that is, the telomere replacement elongation mechanism (ALT) has found an effective tool that can trigger ALT in cancer cells, which can help people understand the specific mechanism of ALT, telomeres are chromosomal end protective structures composed of repetitive DNA, and every time normal cells **, their telomeres will be shortened, and finally when the telomeres are shortened to a certain extent, human ELISA kit cells will stop** or self-destruct.
The vast majority of cancer cells can achieve infinite cell growth by upregulating telomerase (the enzyme responsible for lengthening telomeres).
Approximately 5-15% of cancer cells evade apoptosis through the ALT pathway, and an important hallmark of ALT is the accumulation of RPA2 protein (Replication Protein A2) in a specialized nuclear region called a PML body (promyelocytic leukemia body). The key component in this PML body is the tumor suppressor protein PML. To date, ASF1 has been knocked down in multiple human cell lines.
These cells showed signs of ALT development within three days, with structural alterations in chromatin and RPA2 on the PBL body. ASF1 deficiency was shown to enhance telomere recombination, increase the diversity of telomere length, and reduce the expression of telomerase catalytic subunits. Among them, telomere recombination is the main telomere maintenance mechanism of ALT.
Although ASF1 knockdown is useful, it may not occur naturally because ASF1a and ASF1b are both proteins that are essential for cell survival and proliferation. However, these proteins are involved in chromatin shaping at telomeres, which means that ALT can be activated by interfering with the structure of chromatin. Although it has been speculated that chromatin structure has an effect on ALT, this has not been experimentally proven. The next step will be to knock down ASF1 in more cell lines and even animals in order to further elucidate the regulatory mechanism of the ALT pathway.
If we want to successfully target telomere length or telomerase in cancer**, we need to have a deep understanding of ALT and inhibit this pathway, and this study provides a very practical way to further understand the ALT pathway and develop corresponding inhibitors based on it.