Genomic integrity is a fundamental prerequisite for all living organisms, ensuring the accurate transmission of genetic information and stability of cellular functions across generations. The maintenance of genome integrity relies on a meticulously orchestrated network encompassing a variety of DNA repair factors and pathways. In eukaryotic cells, genomic DNA is assembled into chromatin, a highly organized complex of proteins and DNA. Therefore, chromatin and epigenetic factors have emerged as crucial guardians against genotoxic stress. In this review, we provide a comprehensive summary of the multifaceted roles of H3K9me3, a histone mark associated with silent chromatin, in DNA damage repair and genome maintenance, elucidating its dynamic participation in chromatin organization, silencing of repetitive DNA sequences, and modulation of DNA repair pathways. Importantly, we discuss the potential contribution of H3K9me3 to epigenetic memory following DNA damage, which introduces an additional layer of complexity to our comprehension of genomic surveillance. Finally, we explore the implications of H3K9me3 dysregulation in human cancers and the promising therapeutic avenues that may arise from a nuanced understanding of its function in maintaining genomic stability.
Camptothecin (CPT) is a widely used chemotherapeutic drug that acts by trapping topoisomerase I (TOP1) on DNA during replication. UFMylation is a ubiquitin-like modification involved in various cellular processes, including DNA double-strand break repair. The role of UFMylation in regulating replication-induced DNA damage within cells, however, is unclear. Through in vivo screening, we ascertained that the structure-specific endonuclease MUS81 is UFMylated. MUS81 is responsible for the progression and restarting of replication forks in human cells. We show that CPT triggered the UFMylation of MUS81 at lysine 400, which in turn prevented its ubiquitination-mediated degradation. Additionally, re-expression of WT MUS81, but not UFMylation defective mutant MUS81(K400R), in MUS81-depleted cells rescued CPT-induced cytotoxicity. Thus, the study revealed a new role for UFMylation in CPT-induced DNA damage, in which MUS81 UFMylation at K400 promotes cancer cell survival by inhibiting MUS81 degradation in response to CPT treatment, thus providing an attractive therapeutic strategy combining UFMylation inhibitors with CPT.
BRCA1 and BRCA2 mutations significantly increase the risk of breast and ovarian cancers (OC) by affecting crucial cellular processes such as cell cycle regulation, DNA repair, and apoptosis. Despite understanding their broad impacts, the detailed effects on gene expression and signaling pathways in OC remain unclear. This study aims to elucidate these dynamics by analyzing RNA-Seq data from 24 OC patients with BRCA1/2 mutations and controls using advanced molecular techniques. Differential expression analysis identified 6136 DEGs in BRCA1-mutant and 3615 DEGs in BRCA2-mutant OCs, with 2041 overlapping DEGs. These shared genes underwent Gene Ontology (GO), KEGG, and Protein–protein interaction (PPI) network analyses, revealing pathways like MyD88-independent TLR signaling and mRNA vaccine activation of dendritic cells. Key genes (TRAF3, TICAM1, IRF7, CD40, IRF3, SARM1, RAB11FIP, and PRKCE) involved in TRIF-dependent TLR signaling showed distinct expression patterns in BRCA1/2-deficient OCs. The top 10 hub genes identified were evaluated for their prognostic significance using the Kaplan–Meier Plotter database. The findings highlight the genetic landscape and pathways altered by BRCA1/2 mutations in OC, offering insights for improved diagnostics and personalized treatments. Additionally, the impact on immunosurveillance through the TRIF-dependent TLR system suggests new immunotherapeutic strategies for OC patients with BRCA1/2 mutations, addressing the challenge of cancer recurrence.
Immunotherapy has made remarkable progress within the past decade, but the role of B cells in tumor immunity remains unclear. Here, we show that the combination therapy of anti-PD-1 and TLR9 agonist significantly suppresses the growth of colon and lung tumors in syngeneic mouse models and induces B cell expansion in the tumor-draining lymph nodes and spleen. Using immunological repertoire high-throughput sequencing, we found that combination therapy significantly increased the richness and decreased clonality of B-cell receptors (BCR) with the latter being inversely correlated with the efficacy of tumor inhibition. Moreover, secretory tumor-specific antibodies were increased in combination therapy and elicited Fc-directed tumor lysis function. Employing high-throughput single-cell BCR sequencing technology, we discovered a tumor specific monoclonal antibody (mAb), named 19C5, that had potent anti-tumor activity in vivo. Immunoprecipitation and mass spectrometry analysis revealed that 19C5 mAb specifically recognizes a tumor-associated antigen G protein pathway suppressor 1 (GPS1), whose expression is associated with a worse prognosis in human colon and lung cancer. Taken together, our data highlight the pivotal role of B cells and the production of tumor-reactive antibodies during immunotherapy, suggesting that dynamic changes to the BCR repertoire might serve as a biomarker to predict a clinical response for immunotherapy. We also provide a novel strategy to develop anti-tumor antibodies that may target tumor-associated antigens.