Browsing by Subject "PARP1"

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    PARP1 inhibition preferentially sensitizes spliceosome mutant leukemias through R-loop-associated genomic vulnerabilities
    (2024) Liu, Silvia
    RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here, we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi) despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop–associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription–replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.
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    The role of DNA repair & regulatory proteins in the maintenance of human telomeres and their control of cellular immortalization
    (2017-04) Harvey, Adam
    Telomeres are the nucleoprotein structures that protect the ends of linear chromosomes from recognition as a double-stranded DNA break (DSB). In the absence of proper telomere function, the ends of a chromosome fuse together, creating di-centromeric chromosomes, which can no longer properly segregate at mitosis. Thus, proper telomere maintenance is absolutely essential for all eukaryotic life. Unfortunately, maintaining telomeres at a size that is protective is problematic. For example, as a consequence of “the end-replication problem,” telomeres shorten incrementally during every cell cycle. These short telomeres can, in turn, function to regulate the lifespan of any given cell. Perhaps not surprisingly, therefore, humans have evolved a vast array of genes to enable telomere stability, in order to counteract any premature ageing or cell death. In order to ensure that offspring may begin their life with a default telomere length that is sufficient for stability during the organism’s lifespan, stem cells must not be subjected to overall telomere shortening. Thus, all telomere shortening that a stem cell occurs during its eternal proliferation must be correspondingly compensated for by a lengthening event. This telomere elongation mechanism in essence confers cellular immortality. The most well-characterized of these cellular immortality pathways is controlled by the enzyme telomerase, which precisely elongates telomeres in a stochastic way to maintain a telomere length equilibrium. Unfortunately, this functional, essential pathway can also be conscripted to perform pathological reactions. In human cancer, all malignant growths must enable cellular immortalization to allow for their characteristic uncontrolled proliferation. In most cases this is achieved simply by the reactivation of telomerase. Interestingly, 5 to 15% of all human cancers are telomerase negative. These cancers can be described as ALT cancers, as the Alternative Lengthening of Telomeres pathway enables their immortality. ALT, which is specific to cancer, achieves telomere elongation by aberrant recombination between telomeres. My research has found that DNA repair proteins, such as PARP1, (poly ADP ribose polymerase 1) are critical for both the maintenance of the genome and specifically for proper telomere maintenance. Furthermore, my research has demonstrated that the mutation of a single gene, ATRX, (alpha thalassemia mental retardation on the X chromosome) is an active repressor of ALT immortalization. In summary, I have contributed to the understanding of human telomere length maintenance and these studies have implications for human aging and the genesis of cancer.