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
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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