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| Status |
Public on May 16, 2022 |
| Title |
Disrupted control of origin activation promotes genomic instability upon loss of POLE4 and disfunction of the TRP53-CDKN1A/P21 tumour suppressor axis. |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
The maintenance of genome stability relies on the coordinated control of origin activation and replication fork progression. How the interplay between these processes impacts human genetic disease and cancer remains incompletely characterized. Here we initially show that mouse cells lacking Pole4 and featuring Pole instability exhibit impaired genome-wide activation of DNA replication origins, in a origin location-independent manner. Lack of POLE4 leads to proteasome-dependent Pole degradation prior to CMG (CDC45/MCM2-7/GINS) helicase formation and origin activation. Strikingly, Trp53 ablation in primary Pole4 knock-out cells increased Pole levels and origin activation and reduced DNA damage levels in a transcription-dependent manner. Transcriptome analysis of primary Trp53 knock out cells revealed that the TRP53-CDKN1A/P21 axis maintains appropriate levels of replication initiation factors and CDK activity during unchallenged S-phase. Loss of this control mechanism deregulates origin activation, perturbs genome-wide replication fork progression and induces fork stalling and DNA damage. Thus, while our data support an impaired origin activation model for genetic diseases affecting CMG formation, we propose that loss of the TRP53-CDKN1A/P21 tumour suppressor axis induces inappropriate origin activation and deregulates genome wide fork progression. This phenomenon has broad implications for genetic instability and therapeutic targeting in cancer.
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| Overall design |
Examination of the role of POLE4 in maintaining genome stability
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| Contributor(s) |
Bellelli R |
| Citation(s) |
35649380 |
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| Submission date |
Apr 06, 2022 |
| Last update date |
Aug 16, 2022 |
| Contact name |
Wei Wu |
| Organization name |
Center for Excellence in Molecular Cell Science
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| Department |
Center for Excellence in Molecular Cell Science
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| Street address |
320 yueyang road
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| City |
Shanghai |
| State/province |
Shanghai |
| ZIP/Postal code |
200031 |
| Country |
China |
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| Platforms (1) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA824082 |
