Dataset Information

DNA polymerase θ accomplishes translesion synthesis opposite 1,N⁶-ethenodeoxyadenosine with a remarkably high fidelity in human cells.

ABSTRACT: Here we show that translesion synthesis (TLS) opposite 1,N⁶-ethenodeoxyadenosine (εdA), which disrupts Watson-Crick base pairing, occurs via Polι/Polζ-, Rev1-, and Polθ-dependent pathways. The requirement of Polι/Polζ is consistent with the ability of Polι to incorporate nucleotide opposite εdA by Hoogsteen base pairing and of Polζ to extend synthesis. Rev1 polymerase and Polθ conduct TLS opposite εdA via alternative error-prone pathways. Strikingly, in contrast to extremely error-prone TLS opposite εdA by purified Polθ, it performs predominantly error-free TLS in human cells. Reconfiguration of the active site opposite εdA would provide Polθ the proficiency for error-free TLS in human cells.

SUBMITTER: Yoon JH

PROVIDER: S-EPMC6411006 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

DNA polymerase θ accomplishes translesion synthesis opposite 1,N<sup>6</sup>-ethenodeoxyadenosine with a remarkably high fidelity in human cells.

Yoon Jung-Hoon JH Johnson Robert E RE Prakash Louise L Prakash Satya S

Genes & development 20190226 5-6

Here we show that translesion synthesis (TLS) opposite 1,N<sup>6</sup>-ethenodeoxyadenosine (εdA), which disrupts Watson-Crick base pairing, occurs via Polι/Polζ-, Rev1-, and Polθ-dependent pathways. The requirement of Polι/Polζ is consistent with the ability of Polι to incorporate nucleotide opposite εdA by Hoogsteen base pairing and of Polζ to extend synthesis. Rev1 polymerase and Polθ conduct TLS opposite εdA via alternative error-prone pathways. Strikingly, in contrast to extremely error-pro ...[more]

PMID: 30808656

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Project description:Transcription inhibition by platinum anticancer drugs is an important component of their mechanism of action. Phenanthriplatin, a cisplatin derivative containing phenanthridine in place of one of the chloride ligands, forms highly potent monofunctional adducts on DNA having a structure and spectrum of anticancer activity distinct from those of the parent drug. Understanding the functional consequences of DNA damage by phenanthriplatin for the normal functions of RNA polymerase II (Pol II), the major cellular transcription machinery component, is an important step toward elucidating its mechanism of action. In this study, we present the first systematic mechanistic investigation that addresses how a site-specific phenanthriplatin-DNA d(G) monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps. Pol II processing of the phenanthriplatin lesion differs significantly from that of the canonical cisplatin-DNA 1,2-d(GpG) intrastrand cross-link. A majority of Pol II elongation complexes stall after successful addition of CTP opposite the phenanthriplatin-dG adduct in an error-free manner, with specificity for CTP incorporation being essentially the same as for undamaged dG on the template. A small portion of Pol II undergoes slow, error-prone bypass of the phenanthriplatin-dG lesion, which resembles DNA polymerases that similarly switch from high-fidelity replicative DNA processing (error-free) to low-fidelity translesion DNA synthesis (error-prone) at DNA damage sites. These results provide the first insights into how the Pol II transcription machinery processes the most abundant DNA lesion of the monofunctional phenanthriplatin anticancer drug candidate and enrich our general understanding of Pol II transcription fidelity maintenance, lesion bypass, and transcription-derived mutagenesis. Because of the current interest in monofunctional, DNA-damaging metallodrugs, these results are of likely relevance to a broad spectrum of next-generation anticancer agents being developed by the medicinal inorganic chemistry community.

Dataset Information

DNA polymerase θ accomplishes translesion synthesis opposite 1,N⁶-ethenodeoxyadenosine with a remarkably high fidelity in human cells.

Publications

DNA polymerase θ accomplishes translesion synthesis opposite 1,N<sup>6</sup>-ethenodeoxyadenosine with a remarkably high fidelity in human cells.

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Dataset Information

DNA polymerase θ accomplishes translesion synthesis opposite 1,N6-ethenodeoxyadenosine with a remarkably high fidelity in human cells.

Publications

DNA polymerase θ accomplishes translesion synthesis opposite 1,N<sup>6</sup>-ethenodeoxyadenosine with a remarkably high fidelity in human cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

DNA polymerase θ accomplishes translesion synthesis opposite 1,N⁶-ethenodeoxyadenosine with a remarkably high fidelity in human cells.