Translational Control of the Cancer Genome
How does the “cancer ribosome” modulate translation control leading to human disease and cancer?
A growing list of inherited human syndromes collectively known as “ribosomopathies” share specific pathological features, including cancer predisposition. This intriguing group of diseases, including X-linked Dyskeratosis Congenita (X-DC), cartilage-hair hypoplasia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome and 5q- syndrome, are all characterized by mutations in genes that control fundamental aspects of ribosome synthesis, such as modification and processing of ribosomal RNA (rRNA) as well as ribosome assembly.
An outstanding question is how “defective ribosomes” can lead to such specific pathological features and cancer susceptibility.
Our lab is employing X-DC as a paradigm for understanding how impairments in ribosome function translate into increased cancer susceptibility. Although rRNA is known to be extensively modified through ~200 site specific methylation and pseudouridine modifications, the normal functional role of these modifications as well as their mechanisms of action in controlling ribosome activity is very poorly understood. The gene mutated in X-DC, DKC1, paradoxically encodes the central enzyme that catalyzes this modification in rRNA.
Our lab’s findings revealed that while these rRNA modifications were largely dispensable for general cap-dependent translation, we identified a subset of mRNAs, including the tumor suppressor genes p53 and p27, as well as the anti-apoptotic factors XIAP and Bcl-xL, that rely on ribosome modifications for their accurate translation. Strikingly, these mRNAs all shared a specific and common denominator: the presence of an Internal Ribosome Entry Site (IRES) element within their 5’UTRs. IRES elements are RNA structured elements that can directly recruit the ribosome to the 5’UTR of subsets of distinct mRNAs. We further extended these findings by demonstrating that ribosomes lacking the pseudouridine modification fail to directly bind to IRES elements. Notably, this activity is evolutionarily conserved from yeast to human cells.
How does IRES-dependent translation impact the earliest steps of cellular transformation?
Employing multi-color fluorescent reporters to monitor different modes of translation initiation in vivo, we delineated a switch from cap- to IRES-mediated translation that relies on rRNA modifications during a critical step in cancer formation known as oncogene-induced senescence. This program instructs cells to undergo permanent cell cycle arrest as a mechanism to counteract an oncogenic lesion. Our findings reveal that during the execution of this program, many key tumor suppressor genes, such as p53, contain IRES-elements, which rely on rRNA modifications to be selectively translated.
These findings are seminal in demonstrating that gene expression is tightly regulated by what was once perceived to be a housekeeping, structural component of the ribosome, as well as elucidating how specific perturbations in ribosome activity cause cancer susceptibility.
Our long-term goals seek to delineate whether “cancer ribosomes”, possessing a distinct composition of rRNA modifications, perturb the translation of distinct subgroups of mRNAs that promote cellular transformation. We are also investigating whether ribosomes that are altered in cancer cells “mistranslate” subsets of mRNAs as a mechanism for cancer initiation. We anticipate this work may lead to a paradigm shift in the way the ribosome is conceptualized: from a passive housekeeping machinery to a dynamic regulator controlling the transcript-specific translation of key mRNAs co-opted in cellular transformation.