Currently, breast cancer is the most prevalent cancer globally. Triple-negative breast cancer, a particularly aggressive subtype, often exhibits resistance to radiotherapy, a major cause of treatment failure. The research team of Cai Manbo from the Department of Oncology of the First Affiliated Hospital of University of South China has long been committed to the research on the pathogenesis of triple-negative breast cancerits resistance to radiotherapychemotherapy. On January 28, 2024, Associate Professor Cai Manbo published a research article titled “The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation” inJournal of Biological Chemistry, an internationally renowned journal. In the latest research results, the rolemolecular mechanism of targeting the SETD3-NUDT16 pathway, inhibiting HR repairprotecting stalled replication forks,improving the radiotherapy sensitivity of triple-negative breast cancer cells were clarified.

In this study, SETD3 was identified as a novel substrate of NUDT16, with its stability strictly regulated by NUDT16-mediated dePARylation. The E3 ubiquitin ligase CHFR mediates the recognitiondegradation of endogenous SETD3 through PARP1-dependent PARylation. Mechanistically, SETD3 interacts with BRCA2. During replication stress, it promotes the recruitment of BRCA2 to the stalled replication fork to protect the replication fork from degradation, which contributes to the radiotherapy tolerance of cancer cells. Upon DNA double-strand breaks, SETD3 recruits BRCA2 to the DNA damage sitepromotes homologous recombination repair, resulting in a significant increase in the resistance of cancer cells to radiotherapy. Therefore, the NUDT16-SETD3 pathway plays a key role in inducing radiotherapy resistance. This research provides new ideasexperimental evidence for the radiosensitization of triple-negative breast cancer,has important clinicalscientific significance.

Representative research results

SchematicDiagram of the NUDT16-SETT3 Pathway Regulating Radiotherapy Resistance inTriple-Negative Breast Cancer

The team led by Associate Professor Cai Manbo has long been committed to the mechanism research on the radiotherapychemotherapy resistance of triple-negative breast cancer. In recent years, the team has published several academic papers in important international academic journals such as Drug Resistance Updates,Journal of Biological Chemistry,International Journal of Biological Sciences, andJournal of Translational Medicine. Wu Weijun, a master’s student in the class of 2020, is the first author of the article,Associate Professor Cai Manbo is the first corresponding author. This study was funded by the National Natural Science Foundation of China, the China Scholarship Council, the Natural Science Foundation of Hunan Province, the Hengyang ScienceTechnology Innovation Program,other fundsprojects.