ZSCAN4: A Novel Regulator of Telomere Length in Cancer

Abstract

Replicative immortality is facilitated by telomere maintenance through activating telomerase or by mechanisms collectively called alternative lengthening of telomeres (ALT). Zscan4c regulates telomere length of mouse embryonic stem cells, however, the activity of the human ZSCAN4 and its involvement in cancer is currently unknown. In this work, we describe for the first time the function and mechanism of ZSCAN4 in human cancer. We demonstrate that ZSCAN4 is dysregulated in a variety of cancers, and that ZSCAN4 is required to maintain both culture lifespan in vitro as well as cancer tumor growth in vivo. We further show that ZSCAN4 preferably binds to short telomeres and in conjunction with the telomeric recombination machinery MRE11A and RAD50 forms a complex on the telomere DNA-RNA hybrids. Loss of ZSCAN4 results in gradual telomere shortening which triggers an induction of growth arrest and replicative senescence. Consistently, ZSCAN4 induction increases DNA-RNA hybrids, facilitates telomere recombination events and consequently, telomere extension. Remarkably, we show that ZSCAN4 activates telomere extension irrespective of both telomerase as well as the canonical ALT pathway in cancer cells. Collectively, our work demonstrates a pivotal role for ZSCAN4 in the preservation of cancer replicative lifespan. This work provides the foundation for new approaches to cancer therapies.