DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stress
Abstract Background Replication stress response is crucial for the maintenance of a stable genome. POLDIP3 (DNA polymerase delta interacting protein 3) was initially identified as one of the DNA polymerase δ (Pol δ) interacting proteins almost 20 years ago. Using a variety of in vitro biochemical as...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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| Series: | Animal Models and Experimental Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ame2.12274 |
| _version_ | 1811257556194033664 |
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| author | Sufang Zhang Ernest Y. C. Lee Marietta Y. W. T. Lee Dong Zhang |
| author_facet | Sufang Zhang Ernest Y. C. Lee Marietta Y. W. T. Lee Dong Zhang |
| author_sort | Sufang Zhang |
| collection | DOAJ |
| description | Abstract Background Replication stress response is crucial for the maintenance of a stable genome. POLDIP3 (DNA polymerase delta interacting protein 3) was initially identified as one of the DNA polymerase δ (Pol δ) interacting proteins almost 20 years ago. Using a variety of in vitro biochemical assays, we previously established that POLDIP3 is a key regulator of the enzymatic activity of Pol δ. However, the in vivo function of POLDIP3 in DNA replication and DNA damage response has been elusive. Methods We first generated POLDIP3 knockout (KO) cells using the CRISPR/Cas9 technology. We then investigated its biological functions in vivo using a variety of biochemical and cell biology assays. Results We showed that although the POLDIP3‐KO cells manifest no pronounced defect in global DNA synthesis under nonstress conditions, they are sensitive to a variety of replication fork blockers. Intriguingly, we found that POLDIP3 plays a crucial role in the activation and maintenance of the DNA damage checkpoint in response to exogenous as well as endogenous replication stress. Conclusion Our results indicate that when the DNA replication fork is blocked, POLDIP3 can be recruited to the stalled replication fork and functions to bridge the early DNA damage checkpoint response and the later replication fork repair/restart. |
| first_indexed | 2024-04-12T17:59:17Z |
| format | Article |
| id | doaj.art-6d19d7e2110445ca98accb83a5d04a96 |
| institution | Directory Open Access Journal |
| issn | 2576-2095 |
| language | English |
| last_indexed | 2024-04-12T17:59:17Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Animal Models and Experimental Medicine |
| spelling | doaj.art-6d19d7e2110445ca98accb83a5d04a962022-12-22T03:22:13ZengWileyAnimal Models and Experimental Medicine2576-20952022-10-015546146910.1002/ame2.12274DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stressSufang Zhang0Ernest Y. C. Lee1Marietta Y. W. T. Lee2Dong Zhang3Department of Biochemistry and Molecular Biology New York Medical College New York USADepartment of Biochemistry and Molecular Biology New York Medical College New York USADepartment of Biochemistry and Molecular Biology New York Medical College New York USADepartment of Biomedical Sciences, College of Osteopathic Medicine New York Institute of Technology New York USAAbstract Background Replication stress response is crucial for the maintenance of a stable genome. POLDIP3 (DNA polymerase delta interacting protein 3) was initially identified as one of the DNA polymerase δ (Pol δ) interacting proteins almost 20 years ago. Using a variety of in vitro biochemical assays, we previously established that POLDIP3 is a key regulator of the enzymatic activity of Pol δ. However, the in vivo function of POLDIP3 in DNA replication and DNA damage response has been elusive. Methods We first generated POLDIP3 knockout (KO) cells using the CRISPR/Cas9 technology. We then investigated its biological functions in vivo using a variety of biochemical and cell biology assays. Results We showed that although the POLDIP3‐KO cells manifest no pronounced defect in global DNA synthesis under nonstress conditions, they are sensitive to a variety of replication fork blockers. Intriguingly, we found that POLDIP3 plays a crucial role in the activation and maintenance of the DNA damage checkpoint in response to exogenous as well as endogenous replication stress. Conclusion Our results indicate that when the DNA replication fork is blocked, POLDIP3 can be recruited to the stalled replication fork and functions to bridge the early DNA damage checkpoint response and the later replication fork repair/restart.https://doi.org/10.1002/ame2.12274DNA damage checkpointDNA polymerase deltaPOLDIP3replication stress |
| spellingShingle | Sufang Zhang Ernest Y. C. Lee Marietta Y. W. T. Lee Dong Zhang DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stress Animal Models and Experimental Medicine DNA damage checkpoint DNA polymerase delta POLDIP3 replication stress |
| title | DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stress |
| title_full | DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stress |
| title_fullStr | DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stress |
| title_full_unstemmed | DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stress |
| title_short | DNA polymerase delta interacting protein 3 facilitates the activation and maintenance of DNA damage checkpoint in response to replication stress |
| title_sort | dna polymerase delta interacting protein 3 facilitates the activation and maintenance of dna damage checkpoint in response to replication stress |
| topic | DNA damage checkpoint DNA polymerase delta POLDIP3 replication stress |
| url | https://doi.org/10.1002/ame2.12274 |
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