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Published on: August 30, 2017
Multiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication
Alba Duch1, Berta Canal1, Sonia I Barroso2
1Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), E-08003, Barcelona, Spain.
Abstract:
Conflicts between replication and transcription machineries represent a major source of genomic instability and cells have evolved strategies to prevent such conflicts. However, little is known regarding how cells cope with sudden increases of transcription while replicating. Here, we report the existence of a general mechanism for the protection of genomic integrity upon transcriptional outbursts in S phase that is mediated by Mrc1. The N-terminal phosphorylation of Mrc1 blocked replication and prevented transcription-associated recombination (TAR) and genomic instability during stress-induced gene expression in S phase. An unbiased kinome screening identified several kinases that phosphorylate Mrc1 at the N terminus upon different environmental stresses. Mrc1 function was not restricted to environmental cues but was also required when unscheduled transcription was triggered by low fitness states such as genomic instability or slow growth. Our data indicate that Mrc1 integrates multiple signals, thereby defining a general safeguard mechanism to protect genomic integrity upon transcriptional outbursts.
Insights
Cells use Mrc1 to prevent DNA damage during replication when transcription increases suddenly. N-terminal phosphorylation of Mrc1 halts replication, preventing genomic instability and transcription-associated recombination (TAR).
Area of Science:
- Molecular Biology
- Genomics
- Cellular Stress Response
Background:
- Replication-transcription conflicts are a key source of genomic instability.
- Cellular mechanisms for managing sudden transcription increases during replication are poorly understood.
Purpose of the Study:
- To identify and characterize a general mechanism protecting genomic integrity during S phase.
- To investigate the role of Mrc1 in managing conflicts between replication and transcription.
Main Methods:
- Unbiased kinome screening to identify kinases phosphorylating Mrc1.
- Analysis of Mrc1 phosphorylation at the N terminus.
- Assessment of transcription-associated recombination (TAR) and genomic instability under stress conditions.
Main Results:
- N-terminal phosphorylation of Mrc1 blocks replication and prevents TAR and genomic instability.
- Several kinases were identified that phosphorylate Mrc1 in response to various environmental stresses.
- Mrc1's function is crucial not only for environmental cues but also for unscheduled transcription during low fitness states.
Conclusions:
- Mrc1 acts as a central regulator, integrating multiple signals to safeguard genomic integrity.
- A general mechanism mediated by Mrc1 protects against genomic instability caused by transcriptional outbursts in S phase.
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