PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic Transformation
The regulated formation and resolution of R-loops is a natural process in physiological gene expression. Defects in R-loop metabolism can lead to DNA replication stress, which is associated with a variety of diseases and, ultimately, with cancer. The proteins PARP1, DIDO3, and DHX9 are important pla...
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MDPI AG
2024-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/2/159 |
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| author | Agnes Fütterer Sara Rodriguez-Acebes Juan Méndez Julio Gutiérrez Carlos Martínez-A |
| author_facet | Agnes Fütterer Sara Rodriguez-Acebes Juan Méndez Julio Gutiérrez Carlos Martínez-A |
| author_sort | Agnes Fütterer |
| collection | DOAJ |
| description | The regulated formation and resolution of R-loops is a natural process in physiological gene expression. Defects in R-loop metabolism can lead to DNA replication stress, which is associated with a variety of diseases and, ultimately, with cancer. The proteins PARP1, DIDO3, and DHX9 are important players in R-loop regulation. We previously described the interaction between DIDO3 and DHX9. Here, we show that, in mouse embryonic fibroblasts, the three proteins are physically linked and dependent on PARP1 activity. The C-terminal truncation of DIDO3 leads to the impairment of this interaction; concomitantly, the cells show increased replication stress and senescence. DIDO3 truncation also renders the cells partially resistant to in vitro oncogenic transformation, an effect that can be reversed by immortalization. We propose that PARP1, DIDO3, and DHX9 proteins form a ternary complex that regulates R-loop metabolism, preventing DNA replication stress and subsequent senescence. |
| first_indexed | 2024-03-08T09:55:30Z |
| format | Article |
| id | doaj.art-1316b9e396d14d2ca552216d376e41f5 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T09:55:30Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-1316b9e396d14d2ca552216d376e41f52024-01-29T13:50:27ZengMDPI AGCells2073-44092024-01-0113215910.3390/cells13020159PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic TransformationAgnes Fütterer0Sara Rodriguez-Acebes1Juan Méndez2Julio Gutiérrez3Carlos Martínez-A4Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, SpainDNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, SpainDNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, SpainDepartment of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, SpainDepartment of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, SpainThe regulated formation and resolution of R-loops is a natural process in physiological gene expression. Defects in R-loop metabolism can lead to DNA replication stress, which is associated with a variety of diseases and, ultimately, with cancer. The proteins PARP1, DIDO3, and DHX9 are important players in R-loop regulation. We previously described the interaction between DIDO3 and DHX9. Here, we show that, in mouse embryonic fibroblasts, the three proteins are physically linked and dependent on PARP1 activity. The C-terminal truncation of DIDO3 leads to the impairment of this interaction; concomitantly, the cells show increased replication stress and senescence. DIDO3 truncation also renders the cells partially resistant to in vitro oncogenic transformation, an effect that can be reversed by immortalization. We propose that PARP1, DIDO3, and DHX9 proteins form a ternary complex that regulates R-loop metabolism, preventing DNA replication stress and subsequent senescence.https://www.mdpi.com/2073-4409/13/2/159<i>Dido1</i> geneDIDO3PARP1DHX9replication forkreplication stress |
| spellingShingle | Agnes Fütterer Sara Rodriguez-Acebes Juan Méndez Julio Gutiérrez Carlos Martínez-A PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic Transformation Cells <i>Dido1</i> gene DIDO3 PARP1 DHX9 replication fork replication stress |
| title | PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic Transformation |
| title_full | PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic Transformation |
| title_fullStr | PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic Transformation |
| title_full_unstemmed | PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic Transformation |
| title_short | PARP1, DIDO3, and DHX9 Proteins Mutually Interact in Mouse Fibroblasts, with Effects on DNA Replication Dynamics, Senescence, and Oncogenic Transformation |
| title_sort | parp1 dido3 and dhx9 proteins mutually interact in mouse fibroblasts with effects on dna replication dynamics senescence and oncogenic transformation |
| topic | <i>Dido1</i> gene DIDO3 PARP1 DHX9 replication fork replication stress |
| url | https://www.mdpi.com/2073-4409/13/2/159 |
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