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Activation of ubiquitin-dependent DNA damage bypass is mediated by replication protein a.
- Source :
-
Molecular cell [Mol Cell] 2008 Mar 14; Vol. 29 (5), pp. 625-36. - Publication Year :
- 2008
-
Abstract
- Replicative DNA damage bypass, mediated by the ubiquitylation of the sliding clamp protein PCNA, facilitates the survival of a cell in the presence of genotoxic agents, but it can also promote genomic instability by damage-induced mutagenesis. We show here that PCNA ubiquitylation in budding yeast is activated independently of the replication-dependent S phase checkpoint but by similar conditions involving the accumulation of single-stranded DNA at stalled replication intermediates. The ssDNA-binding replication protein A (RPA), an essential complex involved in most DNA transactions, is required for damage-induced PCNA ubiquitylation. We found that RPA directly interacts with the ubiquitin ligase responsible for the modification of PCNA, Rad18, both in yeast and in mammalian cells. Association of the ligase with chromatin is detected where RPA is most abundant, and purified RPA can recruit Rad18 to ssDNA in vitro. Our results therefore implicate the RPA complex in the activation of DNA damage tolerance.
- Subjects :
- Animals
Cell Cycle physiology
Cell Line
DNA Replication
DNA, Single-Stranded genetics
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Humans
Proliferating Cell Nuclear Antigen genetics
Proliferating Cell Nuclear Antigen metabolism
Replication Protein A genetics
Saccharomyces cerevisiae genetics
Saccharomyces cerevisiae metabolism
Saccharomyces cerevisiae Proteins genetics
Saccharomyces cerevisiae Proteins metabolism
Two-Hybrid System Techniques
Ubiquitin genetics
DNA Damage
DNA, Single-Stranded metabolism
Replication Protein A metabolism
Ubiquitin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 29
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 18342608
- Full Text :
- https://doi.org/10.1016/j.molcel.2007.12.016