Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator
Abstract The DNA damage checkpoint is a highly conserved signaling pathway induced by genotoxin exposure or endogenous genome stress. It alters many cellular processes such as arresting the cell cycle progression and increasing DNA repair capacities. However, cells can downregulate the checkpoint af...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54624-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559328472956928 |
|---|---|
| author | Bingbing Wan Danying Guan Shibai Li Tzippora Chwat-Edelstein Xiaolan Zhao |
| author_facet | Bingbing Wan Danying Guan Shibai Li Tzippora Chwat-Edelstein Xiaolan Zhao |
| author_sort | Bingbing Wan |
| collection | DOAJ |
| description | Abstract The DNA damage checkpoint is a highly conserved signaling pathway induced by genotoxin exposure or endogenous genome stress. It alters many cellular processes such as arresting the cell cycle progression and increasing DNA repair capacities. However, cells can downregulate the checkpoint after prolonged stress exposure to allow continued growth and alternative repair. Strategies that can dampen the DNA damage checkpoint are not well understood. Here, we report that budding yeast employs a pathway composed of the scaffold protein Rtt107, its binding partner Mms22, and an Mms22-associated ubiquitin ligase complex to downregulate the DNA damage checkpoint. Mechanistically, this pathway promotes the proteasomal degradation of a key checkpoint factor, Rad9. Furthermore, Rtt107 binding to Mms22 helps to enrich the ubiquitin ligase complex on chromatin for targeting the chromatin-bound form of Rad9. Finally, we provide evidence that the Rtt107-Mms22 axis operates in parallel with the Rtt107-Slx4 axis, which displaces Rad9 from chromatin. We thus propose that Rtt107 enables a bifurcated “anti-Rad9” strategy to optimally downregulate the DNA damage checkpoint. |
| format | Article |
| id | doaj-art-f5477a6401ad416c88e53f9ef8fd1f18 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f5477a6401ad416c88e53f9ef8fd1f182025-01-05T12:37:43ZengNature PortfolioNature Communications2041-17232025-01-0116111210.1038/s41467-024-54624-0Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediatorBingbing Wan0Danying Guan1Shibai Li2Tzippora Chwat-Edelstein3Xiaolan Zhao4Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityMolecular Biology Program, Memorial Sloan Kettering Cancer CenterMolecular Biology Program, Memorial Sloan Kettering Cancer CenterMolecular Biology Program, Memorial Sloan Kettering Cancer CenterMolecular Biology Program, Memorial Sloan Kettering Cancer CenterAbstract The DNA damage checkpoint is a highly conserved signaling pathway induced by genotoxin exposure or endogenous genome stress. It alters many cellular processes such as arresting the cell cycle progression and increasing DNA repair capacities. However, cells can downregulate the checkpoint after prolonged stress exposure to allow continued growth and alternative repair. Strategies that can dampen the DNA damage checkpoint are not well understood. Here, we report that budding yeast employs a pathway composed of the scaffold protein Rtt107, its binding partner Mms22, and an Mms22-associated ubiquitin ligase complex to downregulate the DNA damage checkpoint. Mechanistically, this pathway promotes the proteasomal degradation of a key checkpoint factor, Rad9. Furthermore, Rtt107 binding to Mms22 helps to enrich the ubiquitin ligase complex on chromatin for targeting the chromatin-bound form of Rad9. Finally, we provide evidence that the Rtt107-Mms22 axis operates in parallel with the Rtt107-Slx4 axis, which displaces Rad9 from chromatin. We thus propose that Rtt107 enables a bifurcated “anti-Rad9” strategy to optimally downregulate the DNA damage checkpoint.https://doi.org/10.1038/s41467-024-54624-0 |
| spellingShingle | Bingbing Wan Danying Guan Shibai Li Tzippora Chwat-Edelstein Xiaolan Zhao Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator Nature Communications |
| title | Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator |
| title_full | Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator |
| title_fullStr | Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator |
| title_full_unstemmed | Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator |
| title_short | Mms22-Rtt107 axis attenuates the DNA damage checkpoint and the stability of the Rad9 checkpoint mediator |
| title_sort | mms22 rtt107 axis attenuates the dna damage checkpoint and the stability of the rad9 checkpoint mediator |
| url | https://doi.org/10.1038/s41467-024-54624-0 |
| work_keys_str_mv | AT bingbingwan mms22rtt107axisattenuatesthednadamagecheckpointandthestabilityoftherad9checkpointmediator AT danyingguan mms22rtt107axisattenuatesthednadamagecheckpointandthestabilityoftherad9checkpointmediator AT shibaili mms22rtt107axisattenuatesthednadamagecheckpointandthestabilityoftherad9checkpointmediator AT tzipporachwatedelstein mms22rtt107axisattenuatesthednadamagecheckpointandthestabilityoftherad9checkpointmediator AT xiaolanzhao mms22rtt107axisattenuatesthednadamagecheckpointandthestabilityoftherad9checkpointmediator |