Fernandez, K. C. | Search bioRxiv

bioRxiv2025

miRISC inhibition causes mitotic defects and synergizes with genotoxic agents in cancers

Although individual microRNAs (miRNAs) can have tumorigenic or tumor-suppressive properties, their overall role in cancer remains controversial. Here, we show that cancer tissues and cell lines are characterized by preferential accumulation of the high-molecular-weight miRNA-induced silencing complex (HMWR), the functionally active form of the effector complex responsible for miRNA-mediated gene repression. Experimentally induced disassembly of the HMWR impairs the growth of human tumor xenografts and of autochthonous tumors in mouse models of human cancer in vivo. Furthermore, disassembly of the HMWR increases chromosome mis-segregation, which synergized with genotoxic agents to potentiate cancer cell vulnerability and improve therapeutic response. These findings suggest pharmacologic inhibition of HMWR as a novel anti-cancer strategy.

cancer biology↗

bioRxiv2022

The Structure-Selective Endonucleases GEN1 and MUS81 are Functionally Complementary in Safeguarding the Genome of Proliferating B Lymphocytes

During the development of humoral immunity, activated B lymphocytes undergo vigorous proliferative, transcriptional, metabolic, and DNA remodeling activities; hence, their genomes are constantly exposed to an onslaught of genotoxic agents and processes. Recombination-dependent DNA transactions that preserve the integrity of the genome and of the DNA replication process generates Holliday junctions that must be eliminated for the accurate segregation of sister chromatids and faithful propagation of genomic material. To investigate the role of two Holliday junction resolvases, GEN1 and MUS81, in B cell biology, we established B-cell conditional knockout mouse models and found that targeted deletion of GEN1 and MUS81 in early B cell precursors halts their development and maturation while selective loss of the resolvases in mature B cells inhibits the generation of robust germinal centers. Upon activation, these double-null mature B lymphocytes fail to proliferate and survive while exhibiting transcriptional signatures of p53 signaling, apoptosis, and type I interferon response. Metaphase spreads of these resolvase-deficient cells showed severe and diverse chromosomal abnormalities, including a preponderance of chromosome breaks, consistent with a defect in resolving DNA recombination intermediates. These observations underscore the essential roles of GEN1 and MUS81 in safeguarding the genome to ensure the proper development and maintenance of B lymphocytes.

immunology↗