Protein arginine methylation, a post-translational modification (PTM), is fundamental in regulating protein function and stability. Among the nine protein methyl transferases (PRMT), PRMT5 plays a critical role in promoting oncogenic processes including tumor proliferation, invasiveness, immune escape and DNA damage repair through different signaling pathways. It is also a target in cancer therapy, with numerous inhibitors in clinical trial. In this review, we focus on the biological functions of PRMT5 in DNA damage repair and maintenance of genome stability in cancer, and summarize the development advance of PRMT5 inhibitors in cancer therapy.
The accumulation of DNA damage and subsequent decline in cellular functions are significant factors contributing to aging and-age associated neurodegeneration. Mutations in the genes involved in DNA repair pathways have been linked to premature aging and age-related neurodegeneration. Although DNA repair mechanisms are remarkably preserved across species, our current knowledge of neuronal-specific DNA repair pathways largely stems from investigations carried out on cellular and animal models, mainly focusing on cancer-related research. While DNA repair mechanisms are generally efficient in correcting damage caused by internal and external sources, the regulation of these mechanisms in post-mitotic neuronal cells, which are non-dividing, is not well understood. Studies utilizing autopsy brain samples have identified specific types of DNA damage and repair proteins in human neurons. However, these findings are inadequate to fully understand the regulatory aspects of neuronal-specific DNA repair pathways. This understanding is crucial for developing mechanism-based drugs that can prevent neuronal cell death, a characteristic feature of neurodegenerative diseases. As a result, further research is required to understand the intricate regulation of the DNA repair mechanisms involved in maintaining genome integrity in neurons. Several chemotherapeutic drugs cause DNA damage or impede cell division and cell death. Drugs that are primarily known to induce DNA damage in dividing cells can also damage neuronal DNA. In this context, we propose that it may be worthwhile to consider the DNA damage response induced by chemotherapy in cancer survivors as a tool to understand definite neuronal DNA repair mechanisms.
Leucine-rich repeat containing protein 59 (LRRC59), a ribosome binding protein located on the endoplasmic reticulum and the nuclear envelope. Although it has been found in blood plasma and linked to the development of a few cancers, the function of LRRC59 is still largely unknown and there is no systematic investigation on its role in various human cancers. We performed a multi-omics data analysis to investigate the expression of LRRC59 in human tumors and its correlation with clinical prognosis, gene set enrichment, mutation status, and immune infiltration in cancers using the TCGA, GTEx, GEPIA2, HPA, UALCAN, Timer2, GTBAdb, cBioPortal database and R packages. In the majority of TCGA tumors, LRRC59 was expressed significantly differently (up-regulated in 25 and down-regulated in 4 cancer types). High LRRC59 expression has been linked to worse prognosis in several malignancies. In numerous carcinomas, the expression of LRRC59 was associated clinicopathological stages. The LRRC59 regulation network was mainly involved in the pathways related to endoplasmic reticulum homeostatic and cell proliferation. In addition, the expression of LRRC59 is also strongly associated with the immune cell infiltration. LRRC59 could also predicts the response to immunotherapy. LRRC59 is a potential valuable biomarker not only for diagnostic and prognostic, but also for immunotherapy in most cancers.
A recent study in Nature Structural and Molecular Biology reveals that chromatin-associated PDHE1α generates acetyl-CoA near DNA double-strand breaks, crucial for chromatin remodeling and DNA repair. PDHE1α recruitment depends on PARP1 and impacts genome stability and cancer therapy resistance. This research sheds light on DNA damage response and chromatin acetylation regulation.
Parental histones, which are modified distinctively from their newly synthesized counterparts, are recycled during DNA replication for the re-establishment of a functional epigenome in the daughter cells. However, the mechanisms and functional implications underlying parental histone deposition onto replicating DNA strands remain enigmatic. A recent study published in Nature reveals a unique pattern of H3K9me3 distribution during DNA replication, which is governed by the human silencing hub (HUSH) complex and DNA polymerase Pol ε. H3K9me3 asymmetry toward the leading strand is important for the silencing of L1 retrotransposons, thus safeguarding both the epigenomic and genomic integrity.