Implications of inhibition of Rev1 interaction with y family DNA polymerases for cisplatin chemotherapy

Jung Hoon Yoon, Robert E. Johnson, Louise Prakash, Satya Prakash

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Pol-or Pol-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Pol. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Pol to block TLS through cisplatin adducts in cancer cells, abrogates Rev1 s ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.

Original languageEnglish (US)
Pages (from-to)1256-1270
Number of pages15
JournalGenes and Development
Volume35
Issue number17-18
DOIs
StatePublished - Sep 1 2021

Keywords

  • Cisplatin intrastrand cross-links
  • DNA repair
  • Nucleotide excision repair
  • Rev1
  • Translesion synthesis
  • Y family DNA polymerases

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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