CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection
Abstract Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43685-2 |
| _version_ | 1827603365994954752 |
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| author | Rishi Kumar Jaiswal Kai-Hang Lei Megan Chastain Yuan Wang Olga Shiva Shan Li Zhongsheng You Peter Chi Weihang Chai |
| author_facet | Rishi Kumar Jaiswal Kai-Hang Lei Megan Chastain Yuan Wang Olga Shiva Shan Li Zhongsheng You Peter Chi Weihang Chai |
| author_sort | Rishi Kumar Jaiswal |
| collection | DOAJ |
| description | Abstract Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing kinase CaMKK2 in response to hydroxyurea/aphidicolin treatment or elevated cytosolic calcium concentration. Cancer-associated STN1 variants impair STN1 phosphorylation, conferring inability of fork protection. Collectively, our study uncovers that CaMKK2 and ATR-CHK1 target STN1 to enable its fork protective function, and suggests an important role of STN1 phosphorylation in cancer development. |
| first_indexed | 2024-03-09T05:37:14Z |
| format | Article |
| id | doaj.art-e1ddd8b0495f4fffbd0f92303089d9ab |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:37:14Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e1ddd8b0495f4fffbd0f92303089d9ab2023-12-03T12:28:04ZengNature PortfolioNature Communications2041-17232023-11-0114111810.1038/s41467-023-43685-2CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resectionRishi Kumar Jaiswal0Kai-Hang Lei1Megan Chastain2Yuan Wang3Olga Shiva4Shan Li5Zhongsheng You6Peter Chi7Weihang Chai8Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of MedicineInstitute of Biochemical Sciences, National Taiwan UniversityOffice of Research, Washington State UniversityDepartment of Radiation Oncology, Rutgers Cancer Institute of New JerseyOffice of Research, Washington State UniversityDepartment of Cell Biology and Physiology, Washington University School of MedicineDepartment of Cell Biology and Physiology, Washington University School of MedicineInstitute of Biochemical Sciences, National Taiwan UniversityDepartment of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of MedicineAbstract Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing kinase CaMKK2 in response to hydroxyurea/aphidicolin treatment or elevated cytosolic calcium concentration. Cancer-associated STN1 variants impair STN1 phosphorylation, conferring inability of fork protection. Collectively, our study uncovers that CaMKK2 and ATR-CHK1 target STN1 to enable its fork protective function, and suggests an important role of STN1 phosphorylation in cancer development.https://doi.org/10.1038/s41467-023-43685-2 |
| spellingShingle | Rishi Kumar Jaiswal Kai-Hang Lei Megan Chastain Yuan Wang Olga Shiva Shan Li Zhongsheng You Peter Chi Weihang Chai CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection Nature Communications |
| title | CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection |
| title_full | CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection |
| title_fullStr | CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection |
| title_full_unstemmed | CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection |
| title_short | CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection |
| title_sort | camkk2 and chk1 phosphorylate human stn1 in response to replication stress to protect stalled forks from aberrant resection |
| url | https://doi.org/10.1038/s41467-023-43685-2 |
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