Modification of PCNA by ISG15 Plays a Crucial Role in Termination of Error-Prone Translesion DNA Synthesis
DNA Replication
0303 health sciences
Binding Sites
DNA Repair
Lysine
Ubiquitin-Protein Ligases
Ubiquitination
Cell Biology
DNA Polymerase II
Arginine
Tripartite Motif Proteins
03 medical and health sciences
Gene Expression Regulation
Mutation Rate
Mutagenesis
Gene Knockdown Techniques
Proliferating Cell Nuclear Antigen
Cytokines
Humans
Molecular Biology
Ubiquitin Thiolesterase
DNA Damage
HeLa Cells
Transcription Factors
DOI:
10.1016/j.molcel.2014.03.031
Publication Date:
2014-04-24T16:00:59Z
AUTHORS (8)
ABSTRACT
In response to DNA damage, PCNA is mono-ubiquitinated and triggers translesion DNA synthesis (TLS) by recruiting polymerase-η. However, it remained unknown how error-prone TLS is turned off after DNA lesion bypass to prevent mutagenesis. Here we showed that ISG15 modification (ISGylation) of PCNA plays a key role in TLS termination. Upon UV irradiation, EFP, an ISG15 E3 ligase, bound to mono-ubiquitinated PCNA and promoted its ISGylation. ISGylated PCNA then tethered USP10 for deubiquitination and in turn the release of polymerase-η from PCNA. Eventually, PCNA was deISGylated by UBP43 for reloading of replicative DNA polymerases and resuming normal DNA replication. However, ISGylation-defective Lys-to-Arg mutations in PCNA or knockdown of any of ISG15, EFP, or USP10 led to persistent recruitment of mono-ubiquitinated PCNA and polymerase-η to nuclear foci, causing an increase in mutation frequency. These findings establish a crucial role of PCNA ISGylation in termination of error-prone TLS for preventing excessive mutagenesis.
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