Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks
| Autor: | Amy Y Zhao, Robert C Wharton, Angela B. Chen, Bryan A Leland, Megan C. King |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA Repair RecQ helicase Cell homologous recombination Cell Cycle Proteins DNA-Directed DNA Polymerase chemistry.chemical_compound 0302 clinical medicine DNA Breaks Double-Stranded Biology (General) Polymerase Genetics 0303 health sciences Microscopy biology RecQ Helicases General Neuroscience Nuclear Proteins General Medicine Chromosomes and Gene Expression 3. Good health Cell biology medicine.anatomical_structure 030220 oncology & carcinogenesis PARP inhibitor Medicine Single-Cell Analysis Exonuclease DNA repair QH301-705.5 Poly ADP ribose polymerase Science Short Report General Biochemistry Genetics and Molecular Biology Resection 03 medical and health sciences Ribose Schizosaccharomyces medicine 030304 developmental biology General Immunology and Microbiology Cancer Cell Biology medicine.disease live cell imaging 030104 developmental biology chemistry Cancer cell Cancer research biology.protein Schizosaccharomyces pombe Proteins Homologous recombination DNA S. pombe |
| Zdroj: | eLife eLife, Vol 7 (2018) |
| ISSN: | 2050-084X |
| Popis: | Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5’ ends of a DSB. For example, loss of either 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2. Here, we develop a single-cell microscopy assay that allows the distinct phases and machineries of resection to be interrogated simultaneously in living S. pombe cells. Using this assay, we find that the 53BP1 orthologue and Rev7 specifically repress long-range resection through the RecQ helicase-dependent pathway, thereby preventing hyper-resection. These results suggest that ‘rewiring’ of BRCA1-deficient cells to employ an Exo1-independent hyper-resection pathway is a driver of PARPi resistance. eLife digest Healthy cells can typically repair damage to their DNA with high accuracy, keeping their genetic code intact. In contrast, cancer cells often lose this ability. Inaccurate repair leads to more frequent DNA mutations, which can make a tumor more aggressive. However, DNA repair-deficient tumors can be targeted with cancer therapies, such as PARP inhibitors, which kill cells that do not have working DNA repair mechanisms. PARP inhibitors show great promise clinically, but unfortunately some tumor cells can become resistant to these treatments over time. Recent work has shown that resistance to PARP inhibitors is often caused by further alternations to DNA repair machineries. Being able to visualize DNA repair in living cells is crucial to understanding this process and to find ways to improve cancer treatments. Previous studies have used repetitive DNA sequences called Lac operators (LacO) to visualize the dynamic behavior of DNA in live cells. Leland et al. have now adapted this system to watch individual DNA repair events in living yeast cells under the microscope. Their experiments reveal that when cells lose a single protein called Rev7, an early phase of DNA repair becomes hyperactive. Leland et al. traced the cause of this hyperactivity to an enzyme in the RecQ helicase family. A RecQ helicase becoming hyperactive in cells lacking Rev7 could explain how some cancer cells become resistant to PARP inhibitor treatments. This information could help fine-tune future approaches to treating cancer. For example, using an inhibitor of RecQ helicase alongside PARP inhibitors may help block this type of resistance from developing in the first place. As well as potentially paving the way for better cancer treatments, this method of visualization could improve scientists’ understanding of the basic processes of DNA repair. |
| Databáze: | OpenAIRE |
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