Results suggest that MDM2 3’UTR elongation may trigger a non-canonical regulatory mechanism that bypasses the traditional MDM2-p53 interaction, and suggests that APA-mediated gene modulation can induce unforeseen compensatory survival pathways in cancer cells, necessitating further investigation into the broader functional landscape of elongated 3'UTRs.
Abstract
This study proposes a novel therapeutic strategy to suppress cancer growth by modulating the MDM2-p53 axis via Alternative Polyadenylation (APA). MDM2 normally promotes tumorigenesis by ubiquitinating and degrading the tumor suppressor p53. In cancer cells, preferential use of proximal polyadenylation signals (PAS) results in shortened 3’UTRs, allowing oncogenic transcripts like MDM2 to evade nuclear sequestration mediated by Inverted Alu (IRAlu) double-stranded RNA structures. We hypothesized that forcing distal PAS usage would elongate the MDM2 mRNA, promoting its nuclear retention and reducing protein translation, thereby restoring p53 activity. Using CRISPR-Cas9, we targeted and deleted the most frequent proximal PAS in the MDM2 3’UTR of A549 cells. Successful genome editing was confirmed via PCR. As expected, Western blot analysis showed a significant reduction in MDM2 expression in PAS-edited cells. However, experimental outcomes contradicted our initial hypothesis: edited cells exhibited higher viability under doxorubicin treatment compared to wild-type cells. Furthermore, despite decreased MDM2 levels, a concurrent reduction in phosphorylated p53 (p-p53) was observed. These unexpected results suggest that MDM2 3’UTR elongation may trigger a non-canonical regulatory mechanism that bypasses the traditional MDM2-p53 interaction. This study highlights the complexity of post-transcriptional regulation and suggests that APA-mediated gene modulation can induce unforeseen compensatory survival pathways in cancer cells, necessitating further investigation into the broader functional landscape of elongated 3’UTRs.
It is concluded that bridging the gap between foundational CRISPR research and its real-world applications is imperative and future efforts should focus on democratizing tools via open-source platforms, advancing delivery systems, and fostering sustainable innovation through synthetic biology integration to fully realize the transformative potential of genome editing in organisms beyond model organisms.
S. Sarsaiya, Archana Jain, Jishuang Chen et al.· Biotechnology Advances· 2 citations
It is argued that formation of a tumour-intrinsic niche is a prerequisite for BRAF-mutant CRC seeding to distant organs and that interference with niche formation may help avoid metastatic relapse.
J. Bugter, L. El Bouazzaoui, E. Küçükköse et al.· bioRxiv· 2 citations
This review summarizes emerging therapeutic strategies for EOC, their mechanisms of action, and their potential to overcome treatment resistance, and covers molecularly targeted therapies, immunotherapies, metabolic and epigenetic approaches, cellular and gene therapies, targeted drug-delivery systems, and locoregional and physical modalities.
Zofia Pietrasik, Mikołaj Kapała, Joanna Pietrasik et al.· Cancers· 0 citations
Genetic engineering (GE) and gene editing may endow traits to trees such as increased biomass and the production of novel biomaterials. Long-lived organisms such as trees might be subject to biotechnology-related risks that could be different than those of annual row crops. Those risks could be relevant to production in engineered plantations and beyond plantations to natural forests. Therefore, appropriate risk regulation is important to assure biosafety of commercialized engineered trees. In addition to gene flow via sexual reproduction, vegetative reproduction might play an additional role in environmental "exposure" risk relative to transgene dispersal in GE tree plantations. While vegetative reproduction is beneficial for preserving desired genetic traits during tree propagation, it may lead to proximal clonal spread in the field. Although the environmental risks associated with vegetative reproduction of GE trees are recognized in commercial forestry, there are few field-based environmental risk assessment (ERA) studies on dispersal risks of self-propagated GE trees. GE or gene editing of target genes involved in the vegetative propagation processes may be useful to mitigate environmental risks of clonal spread through vegetative reproduction. This review provides updates for recent field test results of GE and gene edited trees. Gene candidates related to vegetative reproduction including adventitious shooting (AS) and adventitious rooting (AR) are discussed herein as a means to mitigate unintended clonal spread from GE tree plantations.
Findings establish Cas7-11 as a precise and efficient RNA knockdown tool for functional studies in embryonic development and stem cell biology, providing a versatile alternative to DNA-based gene-editing approaches.
Huan Yan, Imtiaz Ul Hassan, Kai Yan et al.· Cell & Bioscience· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
MIT News · Artificial Intelligence· news.mit.eduAug 17, 2026