Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis

Summary There are significant ambiguities regarding how DNA polymerase η is recruited to DNA lesion sites in stressed cells while avoiding normal replication forks in non-stressed cells. Even less is known about the mechanisms responsible for Pol η-induced mutations in cancer genomes. We show that there are two safeguards to prevent Pol η from adventitious participation in normal DNA replication. These include sequestration by a partner protein and low basal activity. Upon cellular UV irradiation, phosphorylation enables Pol η to be released from sequestration by PDIP38 and activates its polymerase function through increased affinity toward monoubiquitinated proliferating cell nuclear antigen (Ub-PCNA). Moreover, the high-affinity binding of phosphorylated Pol η to Ub-PCNA limits its subsequent displacement by Pol δ. Consequently, activated Pol η replicates DNA beyond the lesion site and potentially introduces clusters of mutations due to its low fidelity. This mechanism could account for the prevalence of Pol η signatures in cancer genome.

• Publication year

  2018

• Venue

  iScience

• Publication date

  2018-07-18

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.isci.2018.07.009PMID 30240625PMCID 6137289
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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