DNA Polymerase Eta and Chemotherapeutic Agents

Chou, Kai Ming

doi:10.1089/ars.2010.3673

Cited by 18 publications

(14 citation statements)

References 73 publications

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“…This is based on conformational transitions of a key positively charged residue coupled with a transient third metal ion at the catalytic site of Pol-η, which ultimately acts as an exit shuttle for the leaving PPi departure. Based on the conservation of these key structural features, this efficient mechanism detected in Pol-η may be shared by several DNA polymerases and other binuclear metalloenzymes for nucleic acid processing ( 25 ), with relevance for the de-novo design of enzymes for DNA processing or the structure-based discovery of small molecules for anti-cancer therapy that targets DNA polymerases in cancer cells ( 71 – 76 ).…”

Section: Discussionmentioning

confidence: 99%

Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η

Genna¹,

Gaspari²,

Peraro

et al. 2016

Nucleic Acids Res

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Trans-lesion synthesis polymerases, like DNA Polymerase-η (Pol-η), are essential for cell survival. Pol-η bypasses ultraviolet-induced DNA damages via a two-metal-ion mechanism that assures DNA strand elongation, with formation of the leaving group pyrophosphate (PPi). Recent structural and kinetics studies have shown that Pol-η function depends on the highly flexible and conserved Arg61 and, intriguingly, on a transient third ion resolved at the catalytic site, as lately observed in other nucleic acid-processing metalloenzymes. How these conserved structural features facilitate DNA replication, however, is still poorly understood. Through extended molecular dynamics and free energy simulations, we unravel a highly cooperative and dynamic mechanism for DNA elongation and repair, which is here described by an equilibrium ensemble of structures that connect the reactants to the products in Pol-η catalysis. We reveal that specific conformations of Arg61 help facilitate the recruitment of the incoming base and favor the proper formation of a pre-reactive complex in Pol-η for efficient DNA editing. Also, we show that a third transient metal ion, which acts concertedly with Arg61, serves as an exit shuttle for the leaving PPi. Finally, we discuss how this effective and cooperative mechanism for DNA repair may be shared by other DNA-repairing polymerases.

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Section: Discussionmentioning

confidence: 99%

Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η

Genna¹,

Gaspari²,

Peraro

et al. 2016

Nucleic Acids Res

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“…In the absence of the accurate replication across DNA damage by pol eta ( 8 ) the mutation frequency by other error prone polymerases increases, accelerating the onset of skin cancer in XP-V patients ( 9 ). Pol eta is also important for the tolerance of other replication-blocking lesions, including thymine glycol ( 10 ), 8-oxoguanine ( 11 ) and those induced by some genotoxic chemotherapeutic agents ( 12 ). Although pol eta is mainly known for its role on TLS, it also participates on homologous recombination ( 13 ) and is involved in the replication of fragile sites ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells

Lerner

Francisco

Soltys

et al. 2016

Nucleic Acids Research

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Genome lesions trigger biological responses that help cells manage damaged DNA, improving cell survival. Pol eta is a translesion synthesis (TLS) polymerase that bypasses lesions that block replicative polymerases, avoiding continued stalling of replication forks, which could lead to cell death. p53 also plays an important role in preventing cell death after ultraviolet (UV) light exposure. Intriguingly, we show that p53 does so by favoring translesion DNA synthesis by pol eta. In fact, the p53-dependent induction of pol eta in normal and DNA repair-deficient XP-C human cells after UV exposure has a protective effect on cell survival after challenging UV exposures, which was absent in p53- and Pol H-silenced cells. Viability increase was associated with improved elongation of nascent DNA, indicating the protective effect was due to more efficient lesion bypass by pol eta. This protection was observed in cells proficient or deficient in nucleotide excision repair, suggesting that, from a cell survival perspective, proper bypass of DNA damage can be as relevant as removal. These results indicate p53 controls the induction of pol eta in DNA damaged human cells, resulting in improved TLS and enhancing cell tolerance to DNA damage, which parallels SOS responses in bacteria.

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“…Interstand adducts are more cytotoxic with estimates to as few as 20 interstrand crosslinks causing cell death if left unrepaired [14]. While more abundant and repaired slower [15;16], intrastrand lesions are better tolerated via HR and bypass polymerases [17]. Repair of intrastrand crosslinks occurs via the NER pathway [4] Therefore, while the exact lesion responsible for clinical efficacy remains to be determined, what is clear is that both NER and HR have differential and contributory roles in the cellular sensitivity to cisplatin.…”

Section: Introductionmentioning

confidence: 99%

Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer

Mishra

Dormi

Turchi

et al. 2015

Biochemical Pharmacology

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Platinum-based chemotherapeutics exert their therapeutic efficacy via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. Repair and tolerance of these Pt-DNA lesions by nucleotide excision repair (NER) and homologous recombination (HR) can substantially reduce the effectiveness of therapy. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt treatment and increase clinical efficacy. Replication Protein A (RPA) plays essential roles in both NER and HR, along with its role in DNA replication and DNA damage checkpoint activation. Each of these functions is, in part, mediated by RPA binding to single-stranded DNA (ssDNA). Here we report the synthesis and characterization of novel derivatives of RPA small molecule inhibitors and their activity in models of epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC). We have synthesized analogs of our previously reported RPA inhibitor TDRL-505 and determined the structure activity relationships. These data led us to the identification of TDRL-551, which exhibited a greater than 2-fold increase in in vitro activity. TDRL-551 showed synergy with Pt in tissue culture models of EOC and in vivo efficacy, as a single agent and in combination with platinum, in a NSCLC xenograft model. These data demonstrate the utility of RPA inhibition in EOC and NSCLC and the potential in developing novel anticancer therapeutics that target RPA-DNA interactions.

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DNA Polymerase Eta and Chemotherapeutic Agents

Cited by 18 publications

References 73 publications

Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η

Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η

Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells

Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer

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