Telomere Maintenance and the cGAS-STING Pathway in Cancer

Abstract

Cancer cells exhibit the unique characteristics of high proliferation and aberrant DNA damage response, which prevents cancer therapy from effectively eliminating them. The machinery required for telomere maintenance, such as telomerase and the alternative lengthening of telomeres (ALT), enables cancer cells to proliferate indefinitely. In addition, the molecules in this system are involved in noncanonical pro-tumorigenic functions. Of these, the function of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contains telomere-related molecules, is a well-known contributor to the tumor microenvironment (TME). This review summarizes the current knowledge of the role of telomerase and ALT in cancer regulation, with emphasis on their noncanonical roles beyond telomere maintenance. The components of the cGAS-STING pathway are summarized with respect to intercell communication in the TME. Elucidating the underlying functional connection between telomere-related molecules and TME regulation is important for the development of cancer therapeutics that target cancer-specific pathways in different contexts. Finally, strategies for designing new cancer therapies that target cancer cells and the TME are discussed.

Keywords: ALT; DNA damage; cGAS-STING; cancer; cellular senescence; telomere.

Figure 1

Overview of the connections between telomere maintenance and the cGAS-STING pathway in the nucleus and mitochondria of cancer cells. Cancer cells overcome the proliferation limit from telomere shortening by telomere maintenance mechanisms. Molecules involved in telomere maintenance also have noncanonical functions in the mitochondria. The mitochondrial functions of telomere-related molecules protect cancer cells from various stresses. The long-lasting cancer cells change the surrounding environment pro-tumorigenic by the activation of the cGAS-STING pathway in normal cells surrounding cancer cells, as well as in cancer cells.

Figure 2

Telomere maintenance in cancer cells. Schematic images of (A) the telomerase complex and (B) pathways associated with telomerase and ALT in cancer cells. Cancer cells overcome telomere shortening by telomere maintenance mechanisms such as telomerase and ALT. In the telomerase complex, the telomerase RNA component TERC has the H/ACA motif and recruits the H/ACA proteins to stabilize the complex. In ALT, telomere lengthening is mediated by the HR-based DNA repair machinery. Molecules in the telomere maintenance also show the mitochondrial functions. In addition, cytosolic dsDNA fractions known as ECTR, which are produced from ALT, trigger the cGAS-STING pathway.

Figure 3

Overview of the cGAS-STING pathway in cancer cells and surrounding cells. Pro-tumorigenic TME in cancer from chronical inflammation by the cGAS-STING pathway in cancer cells and normal cells surrounding them. Genome instability and damaged mitochondria in cancer cells produce cytosolic dsDNA, which activates the cGAS DNA sensor. cGAS turns ATP and GTP to cGAMP, which activates STING on the ER membrane. The activated STING translocates to Golgi and recruits TBK1, which phosphorylates IRF3. The phosphorylated IRF3 promotes the expression of inflammatory factors, which results in the inflammatory environment. The inflammatory factors also activate oncogenes in normal cells surrounding the cancer cells, which triggers the cGAS-STING pathway in the normal cells. The chain reaction of inflammation creates the pro-tumorigenic TME in cancer.