Resolution of telomeric nucleotide structure barriers by specific structure nucleases

National Institute On Aging

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Abstract

We have begun to characterize the role of a RNA binding protein WY2, in telomere protection in unique human cancers that are engaged in telomere length maintenance via the alternative lengthening of telomeres (ALT), a homology-directed telomere maintenance pathway. Telomeres in ALT cells exhibit an inherent susceptibility to replication stress. Our results identified that ALT cells are highly enriched for WY2, especially with replication stress. Our ongoing projects aim to investigate the mechanistic basis of WY2 in protecting telomere integrity by employing ALT cells with WY2 depletion or expressing specific disruption of WY2. Our preliminary data show that disrupting the telomeric localization of WY2 enhances DNA/RNA hybrids at telomeres, leading to replication-dependent telomere loss and drastic increase in telomere-dysfunction induced DNA damage response. In addition, WY2 deficiency downregulates telomeric protein components. These findings demonstrate that WY2 is a novel regulator of telomere length maintenance in human ALT cancers. We will continue to explore the mechanism by which WY2 ensures telomere length maintenance in human ALT cancers.