Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass
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Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass. / Povlsen, Lou K; Beli, Petra; Wagner, Sebastian A; Poulsen, Sara L; Sylvestersen, Kathrine B; Poulsen, Jon Wriedt; Nielsen, Michael L; Bekker-Jensen, Simon; Mailand, Niels; Choudhary, Chuna Ram.
In: Nature Cell Biology, Vol. 14, No. 10, 10.2012, p. 1089-98.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass
AU - Povlsen, Lou K
AU - Beli, Petra
AU - Wagner, Sebastian A
AU - Poulsen, Sara L
AU - Sylvestersen, Kathrine B
AU - Poulsen, Jon Wriedt
AU - Nielsen, Michael L
AU - Bekker-Jensen, Simon
AU - Mailand, Niels
AU - Choudhary, Chuna Ram
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
KW - Carrier Proteins
KW - Cell Line
KW - DNA Damage
KW - DNA Repair
KW - DNA Replication
KW - DNA-Directed DNA Polymerase
KW - Humans
KW - Lysine
KW - Proteasome Endopeptidase Complex
KW - S Phase
KW - Signal Transduction
KW - Ubiquitination
KW - Ultraviolet Rays
U2 - 10.1038/ncb2579
DO - 10.1038/ncb2579
M3 - Journal article
C2 - 23000965
VL - 14
SP - 1089
EP - 1098
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 10
ER -
ID: 46282763