Browsing by Subject "nucleotide excision repair"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    eIF3a Regulates De Novo Fatty Acid Synthesis as an Alternative Mechanism in Cisplatin Response in Non-Small Cell Lung Cancer Cells
    (2024-08) Gu, Boqing; Jerde, Travis; Lu, Tao; Safa, Ahmad R.; Zhang, Jian-Ting; Wek, Ronald C.
    eIF3a is known to modulate DNA damage repair and cancer chemotherapy resistance partially via translational regulation of Raptor and its downstream mTOR pathway activity. Fatty acid synthase (FASN) has recently been reported to exert negative feedback on the mTOR signaling pathway, and FASN overexpression is associated with reduced chemotherapy efficiency in multiple cancer types. Here, we show that eIF3a exerts additional regulation on mTOR signaling pathway and chemotherapy resistance in non-small cell lung cancer by inhibiting FASN-mediated de novo lipid synthesis. Through genetic and chemical manipulations, we demonstrate that eIF3a physically interacts with the 5’-UTR of FASN mRNA to prevent FASN protein synthesis. Furthermore, FASN downregulation by eIF3a results in accumulation of malonyl-CoA, a substrate for fatty acid synthesis, which in turn directly inhibits mTOR activity of mTORC1 complex, decreasing NER protein level and cellular sensitivity to cisplatin in an eIF3a-dependent manner in addition to eIF3a-regulated expression of Raptor subunit in mTORC1. Taken together, our findings reveal a direct translational control of FASN-mediated fatty acid metabolism, suggesting a multi-level eIF3a regulatory paradigm on NER protein synthesis and activity during cancer cell response to cisplatin treatment.
  • Thumbnail Image
    Item
    Integration of DNA Damage and Repair with Murine Double-Minute 2 (Mdm2) in Tumorigenesis
    (MDPI, 2012-12-03) Lehman, Jason A.; Mayo, Lindsey D.; Pediatrics, School of Medicine
    The alteration of tumorigenic pathways leading to cancer is a degenerative disease process typically involving inactivation of tumor suppressor proteins and hyperactivation of oncogenes. One such oncogenic protein product is the murine double-minute 2, or Mdm2. While, Mdm2 has been primarily associated as the negative regulator of the p53 tumor suppressor protein there are many p53-independent roles demonstrated for this oncogene. DNA damage and chemotherapeutic agents are known to activate Mdm2 and DNA repair pathways. There are five primary DNA repair pathways involved in the maintenance of genomic integrity: Nucleotide excision repair (NER), Base excision repair (BER), Mismatch repair (MMR), Non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we will briefly describe these pathways and also delineate the functional interaction of Mdm2 with multiple DNA repair proteins. We will illustrate the importance of these interactions with Mdm2 and discuss how this is important for tumor progression, cellular proliferation in cancer.