PCNA Deubiquitylases Control DNA Damage Bypass at Replication Forks
[EN]DNA damage tolerance plays a key role in protecting cell viability through translesion synthesis and template switching-mediated bypass of genotoxic polymerase-blocking base lesions. Both tolerance pathways critically rely on ubiquitylation of the proliferating-cell nuclear antigen (PCNA) on lys...
| Authors: | , , , , , |
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| Format: | article |
| Status: | Published version |
| Publication Date: | 2019 |
| Country: | España |
| Institution: | Universidad de Salamanca (USAL) |
| Repository: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/154776 |
| Online Access: | http://hdl.handle.net/10366/154776 |
| Access Level: | Open access |
| Keyword: | Cell Cycle DNA Replication PCNA PCNA-Deubiquitylases 2415 Biología Molecular 2407 Biología Celular 2302 Bioquímica 2409 Genética ciclo celular replicación del ADN |
| Summary: | [EN]DNA damage tolerance plays a key role in protecting cell viability through translesion synthesis and template switching-mediated bypass of genotoxic polymerase-blocking base lesions. Both tolerance pathways critically rely on ubiquitylation of the proliferating-cell nuclear antigen (PCNA) on lysine 164 and have been proposed to operate uncoupled from replication. We report that Ubp10 and Ubp12 ubiquitin proteases differentially cooperate in PCNA deubiquitylation, owing to distinct activities on PCNAlinked ubiquitin chains. Ubp10 and Ubp12 associate with replication forks in a fashion determined by Ubp10 dependency on lagging-strand PCNA residence, and they downregulate translesion polymerase recruitment and template switch events engaging nascent strands. These findings reveal PCNAK164 deubiquitylation as a key mechanism for the modulation of lesion bypass during replication, which might set a framework for establishing strand-differential pathway choices. We propose that damage tolerance is tempered at replication forks to limit the extension of bypass events and sustain chromosome replication rates. |
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