RNF8 has both KU-dependent and independent roles in chromosomal break repair
| Autor: | Carlos Mendez-Dorantes, Felicia Wednesday Lopezcolorado, Jeremy M. Stark, Eva Jahanshir, Ragini Bhargava, Linda Jillianne Tsai |
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| Rok vydání: | 2020 |
| Předmět: |
DNA End-Joining Repair
AcademicSubjects/SCI00010 Ubiquitin-Protein Ligases PALB2 Cell Cycle Proteins DNA-Directed DNA Polymerase Genome Integrity Repair and Replication PALB2 Gene Resection 03 medical and health sciences 0302 clinical medicine INDEL Mutation Protein Domains Ubiquitin RNA interference Genetics Humans DNA Breaks Double-Stranded Ku Autoantigen Sequence Deletion 030304 developmental biology Double strand 0303 health sciences biology BRCA1 Protein Nuclear Proteins Recombinational DNA Repair Chromosome Breakage Cell biology Ubiquitin ligase DNA-Binding Proteins biology.protein RNA Interference Rad51 Recombinase Signal transduction Fanconi Anemia Complementation Group N Protein Tumor Suppressor p53-Binding Protein 1 030217 neurology & neurosurgery |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkaa380 |
| Popis: | Chromosomal double strand breaks (DSBs) can initiate several signaling events, such as ubiquitination, however the precise influence of such signaling on DSB repair outcomes remains poorly understood. With an RNA interference screen, we found that the E3 ubiquitin ligase RNF8 suppresses a deletion rearrangement mediated by canonical non-homologous end joining (C-NHEJ). We also found that RNF8 suppresses EJ without insertion/deletion mutations, which is a hallmark of C-NHEJ. Conversely, RNF8 promotes alternative EJ (ALT-EJ) events involving microhomology that is embedded from the edge of the DSB. These ALT-EJ events likely require limited end resection, whereas RNF8 is not required for single-strand annealing repair involving extensive end resection. Thus, RNF8 appears to specifically facilitate repair events requiring limited end resection, which we find is dependent on the DSB end protection factor KU. However, we also find that RNF8 is important for homology-directed repair (HDR) independently of KU, which appears linked to promoting PALB2 function. Finally, the influence of RNF8 on EJ is distinct from 53BP1 and the ALT-EJ factor, POLQ. We suggest that RNF8 mediates both ALT-EJ and HDR, but via distinct mechanisms, since only the former is dependent on KU. |
| Databáze: | OpenAIRE |
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