CDC20 Holds Novel Regulation Mechanism in RPA1 during Different Stages of DNA Damage to Induce Radio-Chemoresistance.

Targeting CDC20 can enhance the radiosensitivity of tumor cells, but the function and mechanism of CDC20 on DNA damage repair response remains vague. To examine that issue, tumor cell lines, including KYSE200, KYSE450, and HCT116, were utilized to detect the expression, function, and underlying mechanism of CDC20 in radio-chemoresistance. Western blot and immunofluorescence staining were employed to confirm CDC20 expression and location, and radiation could upregulate the expression of CDC20 in the cell nucleus. The homologous recombination (HR) and non-homologous end joining (NHEJ) reporter gene systems were utilized to explore the impact of CDC20 on DNA damage repair, indicating that CDC20 could promote HR repair and radio/chemo-resistance. In the early stages of DNA damage, CDC20 stabilizes the RPA1 protein through protein-protein interactions, activating the ATR-mediated signaling cascade, thereby aiding in genomic repair. In the later stages, CDC20 assists in the subsequent steps of damage repair by the ubiquitin-mediated degradation of RPA1. CCK-8 and colony formation assay were used to detect the function of CDC20 in cell vitality and proliferation, and targeting CDC20 can exacerbate the increase in DNA damage levels caused by cisplatin or etoposide. A tumor xenograft model was conducted in BALB/c-nu/nu mice to confirm the function of CDC20 in vivo, confirming the in vitro results. In conclusion, this study provides further validation of the potential clinical significance of CDC20 as a strategy to overcome radio-chemoresistance via uncovering a novel role of CDC20 in regulating RPA1 during DNA damage repair.

Therapeutic potential of natural antisense transcripts and various mechanisms involved for clinical applications and disease prevention.

Antisense transcription, a prevalent occurrence in mammalian genomes, gives rise to natural antisense transcripts (NATs) as RNA molecules. These NATs serve as agents of diverse transcriptional and post-transcriptional regulatory mechanisms, playing crucial roles in various biological processes vital for cell function and immune response. However, when their normal functions are disrupted, they can contribute to human diseases. This comprehensive review aims to establish the molecular foundation linking NATs to the development of disorders like cancer, neurodegenerative conditions, and cardiovascular ailments. Additionally, we evaluate the potential of oligonucleotide-based therapies targeting NATs, presenting both their advantages and limitations, while also highlighting the latest advancements in this promising realm of clinical investigation.Abbreviations: NATs- Natural antisense transcripts, PRC1- Polycomb Repressive Complex 1, PRC2- Polycomb Repressive Complex 2, ADARs- Adenosine deaminases acting on RNA, BDNF-AS- Brain-derived neurotrophic factor antisense transcript, ASOs- Antisense oligonucleotides, SINEUPs- Inverted SINEB2 sequence-mediated upregulating molecules, PTBP1- Polypyrimidine tract binding protein-1, HNRNPK- heterogeneous nuclear ribonucleoprotein K, MAPT-AS1- microtubule-associated protein tau antisense 1, KCNQ1OT- (KCNQ1 opposite strand/antisense transcript 1, ERK- extracellular signal-regulated kinase 1, USP14- ubiquitin-specific protease 14, EGF- Epidermal growth factor, LSD1- Lysine Specific Demethylase 1, ANRIL- Antisense Noncoding RNA in the INK4 Locus, BWS- Beckwith-Wiedemann syndrome, VEGFA- Vascular Endothelial Growth component A.