Resolution of telomeric nucleotide structure barriers by specific structure nucleases

National Institute On Aging

Investigators

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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 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. A manuscript is in preparation and will submitted for publication soon. In addition, we have assisted Dr. Kathrin Muegge's laboratory at National Cancer Institute in investigating the epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation (Nat Commun. 2021, 12:3520-3536. PMID: 34112784. PMCID: PMC8192551). In collaboration with Dr. Elizabeth A Sierra Potchanant in Indiana University School of Medicine, we have investigated mitotic Errors in promoting Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia (Front Oncol. 2021,11:752933)