p53 Maintains Genomic Stability by Preventing Interference between Transcription and Replication
| Autor: | Irina Alexander, Chit Fang Cheok, Vincent H.B. Ho, Kanda Sangthongpitag, Zhaoru Lin, Constance Qiao Xin Yeo, Ramesh Kumar, Vishal Pendharkar, Obed Akwasi Aning, Shuhui Lim |
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| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DNA re-replication DNA Replication Transcription Genetic DNA damage Topoisomerase Inhibitors Eukaryotic DNA replication Gyrase Inhibitor Biology General Biochemistry Genetics and Molecular Biology Genomic Instability 03 medical and health sciences Replication factor C Control of chromosome duplication Antigens Neoplasm Humans Science::Medicine [DRNTU] Poly-ADP-Ribose Binding Proteins lcsh:QH301-705.5 Protein p53 Topoisomerase DNA replication HCT116 Cells Molecular biology Cell biology DNA-Binding Proteins 030104 developmental biology DNA Topoisomerases Type II lcsh:Biology (General) biology.protein Origin recognition complex Tumor Suppressor Protein p53 |
| Zdroj: | Cell Reports, Vol 15, Iss 1, Pp 132-146 (2016) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2016.03.011 |
| Popis: | p53 tumor suppressor maintains genomic stability, typically acting through cell-cycle arrest, senescence, and apoptosis. We discovered a function of p53 in preventing conflicts between transcription and replication, independent of its canonical roles. p53 deficiency sensitizes cells to Topoisomerase (Topo) II inhibitors, resulting in DNA damage arising spontaneously during replication. Topoisomerase IIα (TOP2A)-DNA complexes preferentially accumulate in isogenic p53 mutant or knockout cells, reflecting an increased recruitment of TOP2A to regulate DNA topology. We propose that p53 acts to prevent DNA topological stress originating from transcription during the S phase and, therefore, promotes normal replication fork progression. Consequently, replication fork progression is impaired in the absence of p53, which is reversed by transcription inhibition. Pharmacologic inhibition of transcription also attenuates DNA damage and decreases Topo-II-DNA complexes, restoring cell viability in p53-deficient cells. Together, our results demonstrate a function of p53 that may underlie its role in tumor suppression. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version |
| Databáze: | OpenAIRE |
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