ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress
| Autor: | Su Hyung Park, Sungchul Hohng, Minwoo Wie, Sukhyun Kang, KS Lee, Deokjae Lee, Jun Hong Park, Jae Sun Ra, In Bae Park, Sunyoung Hwang, Eun-Ho Song, Kyungjae Myung, Jieun Park, Eun A. Lee, Nalae Kang |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
0301 basic medicine Genome instability DNA Repair DNA repair Science RAD51 General Physics and Astronomy DNA damage response Article Genomic Instability General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Proliferating Cell Nuclear Antigen Fluorescence Resonance Energy Transfer Humans Hydroxyurea RNA Small Interfering lcsh:Science Multidisciplinary biology DNA Breaks HEK 293 cells Stalled forks General Chemistry Flow Cytometry Single Molecule Imaging Deoxyuridine Cell biology Proliferating cell nuclear antigen DNA-Binding Proteins HEK293 Cells 030104 developmental biology Bromodeoxyuridine chemistry Gene Knockdown Techniques biology.protein ATPases Associated with Diverse Cellular Activities Replisome Fork (file system) lcsh:Q Rad51 Recombinase 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Maintaining stability of replication forks is important for genomic integrity. However, it is not clear how replisome proteins contribute to fork stability under replication stress. Here, we report that ATAD5, a PCNA unloader, plays multiple functions at stalled forks including promoting its restart. ATAD5 depletion increases genomic instability upon hydroxyurea treatment in cultured cells and mice. ATAD5 recruits RAD51 to stalled forks in an ATR kinase-dependent manner by hydroxyurea-enhanced protein-protein interactions and timely removes PCNA from stalled forks for RAD51 recruitment. Consistent with the role of RAD51 in fork regression, ATAD5 depletion inhibits slowdown of fork progression and native 5-bromo-2ʹ-deoxyuridine signal induced by hydroxyurea. Single-molecule FRET showed that PCNA itself acts as a mechanical barrier to fork regression. Consequently, DNA breaks required for fork restart are reduced by ATAD5 depletion. Collectively, our results suggest an important role of ATAD5 in maintaining genome integrity during replication stress. How the replisome machinery contributes to fork stability under replication stress is currently not clear. Here the authors reveal a role for ATAD5 in maintaining genome integrity during replication stress by promoting replication restart through RAD51/PCNA regulation. |
| Databáze: | OpenAIRE |
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