Implications Of Inhibition Of Rev1 Interaction With Y Family Dna Polymerases For Cisplatin Chemotherapy
GENES & DEVELOPMENT(2021)
摘要
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 eta- or Pol(iota)-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Pol zeta. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Pol zeta 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.
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关键词
DNA repair, nucleotide excision repair, translesion synthesis, Y family DNA polymerases, cisplatin intrastrand cross-links, Rev1
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