Autism-Associated Vigilin Depletion Impairs DNA Damage Repair
| Autor: | Raj K. Pandita, Krishna P. Bhat, Albino Bacolla, Vijay Charaka, Sadaf Jan, Shahid Banday, Tej K. Pandita, Arjamand Mushtaq, Mohammad Altaf, Ganesh Rao, Ulfat Syed Mir, Dharmendra Kumar Singh, Clayton R. Hunt, John A. Tainer |
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| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
Genome instability DNA Repair DNA repair DNA damage RAD51 Biology Proto-Oncogene Mas Genomic Instability 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Humans DNA Breaks Double-Stranded Autistic Disorder Molecular Biology 030304 developmental biology 0303 health sciences DNA synthesis BRCA1 Protein RNA-Binding Proteins Cell Biology Cell biology Histone chemistry biology.protein Rad51 Recombinase Homologous recombination 030217 neurology & neurosurgery DNA Research Article |
| Zdroj: | Mol Cell Biol |
| ISSN: | 1098-5549 |
| Popis: | Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders. |
| Databáze: | OpenAIRE |
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