Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass

Research output: Contribution to journalJournal articleResearchpeer-review

Lou K Povlsen, Petra Beli, Sebastian A Wagner, Sara L Poulsen, Kathrine B Sylvestersen, Jon Wriedt Poulsen, Michael L Nielsen, Simon Bekker-Jensen, Niels Mailand, Chuna Ram Choudhary

Protein ubiquitylation has emerged as a key regulatory mechanism in DNA-damage signalling and repair pathways. We report a proteome-wide, site-specific survey of ubiquitylation changes after ultraviolet irradiation, identifying numerous upregulated and downregulated ubiquitylation sites on known components of DNA-damage signalling, as well as on proteins not previously implicated in this process. Our results uncover a critical role for PCNA-associated factor PAF15 (p15(PAF)/KIAA0101) ubiquitylation during DNA replication. During unperturbed S phase, chromatin-associated PAF15 is modified by double mono-ubiquitylation of Lys 15 and 24 templated through PCNA binding. Replication blocks trigger rapid, proteasome-dependent removal of Lys 15/24-ubiquitylated PAF15 from PCNA, facilitating bypass of replication-fork-blocking lesions by allowing recruitment of translesion DNA synthesis polymerase polη to mono-ubiquitylated PCNA at stalled replisomes. Our findings demonstrate widespread involvement of ubiquitin signalling in genotoxic-stress responses and identify a critical function for dynamic PAF15 ubiquitylation in safeguarding genome integrity when DNA replication is challenged.
Original languageEnglish
JournalNature Cell Biology
Volume14
Issue number10
Pages (from-to)1089-98
Number of pages10
ISSN1465-7392
DOIs
Publication statusPublished - Oct 2012

    Research areas

  • Carrier Proteins, Cell Line, DNA Damage, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, Humans, Lysine, Proteasome Endopeptidase Complex, S Phase, Signal Transduction, Ubiquitination, Ultraviolet Rays

ID: 46282763