A new study has highlighted the critical role of a protein called cyclin F in controlling DNA repair during different phases of the cell cycle: August 2024 Image Docking of EXO1 peptide to cyclin F protein using COSMIC2 When cells are exposed to ionizing radiation, it can cause severe damage by creating breaks in both strands of the DNA double helix, known as double-strand breaks (DSBs).Cells have developed several mechanisms to repair these breaks. The two primary methods are homologous recombination (HR), which uses a template DNA strand to guide repair, and non-homologous end joining (NHEJ), which does not require a template.There are also backup repair methods such as microhomology-mediated end joining (MMEJ) and single-strand annealing (SSA). However, the process by which cells choose between these different repair methods is not well understood.Researchers Professor Vincenzo D’Angiolella and Paul Smith, in Edinburgh Cancer Research at the Institute of Genetics and Cancer, used a gene-editing tool called CRISPR to systematically address the role of around 800 ubiquitin system genes in repairing DNA after exposure to ionizing radiation. Ubiquitination is a process where a molecule called ubiquitin is attached to a protein, altering its function or marking it for degradation. By systematically disrupting genes involved in the ubiquitin system, the researchers identified which genes are essential for cell survival following radiation damage.They found that cyclin F, an E3 ubiquitin ligase, mediates the degradation of another protein called EXO1 during mitosis, the stage of the cell cycle when cells are dividing. This is an important finding: in the absence of cyclin F, cells have an excess of EXO1 and enter the next cell cycle with damaged chromosomes as they are unable to repair DSBs.In addition to the implications the discovery has for fundamental biology (this process happens in all cells), this mechanism highlights a vulnerability of cancer cells which may be exploited in cancer treatment in combination with radiation to improve patient responses.This discovery has an immediate application in glioblastoma where half of the patients don't respond to temozolomide in combination with radiotherapy. The list of genes identified is a good guideline of novel targets. “It also benefits drug developers as they can identify which target genes could be inhibited to augment the killing effect of radiotherapy.Professor Vincenzo D’AngiolellaCharles and Ethel Barr Chair of Cancer ResearchLinksProfessor Vincenzo D’Angiolella groupRead the full paper in Science Advances (external link) Tags 2024 Publication date 16 Aug, 2024
