In this proposal I will explore the mechanisms whereby dysregulation of abundant small noncoding RNAs, H/ACA small RNAs, alters gene expression at the post-transcriptional level contributing to tumorigenesis. H/ACA small RNAs associate with core proteins, generating a multitude of small ribonucleoprotein particles (RNPs) with essential roles in mRNA translation, splicing and telomere maintenance. Importantly, dysregulation of H/ACA small RNPs is emerging as a common feature of human cancers. Despite these findings, how defects in H/ACA small RNPs contribute to tumorigenesis is completely unknown.
My preliminary data suggest that H/ACA small RNPs are essential components of an important step of tumor suppression, oncogene-induced senescence (OIS), and identify novel categories of mRNAs regulated at the translation level downstream of H/ACA small RNPs. Interestingly, these mRNAs encode splicing factors altered in malignancies associated with hematopoietic stem cell (HSC) defects. These data support my hypothesis that H/ACA small RNPs are key functional components of a “fail-safe” anti-oncogenic gene expression program. Here I will delineate the mechanisms underlying H/ACA small RNP regulation during OIS in HSCs and determine the impact of their impairments on human leukemogenesis. These studies will unravel a new facet of gene regulation and have broad implications for the therapeutic intervention of human syndromes and cancers characterized by HSC dysfunction.