hPrimpol1/CCDC111 is a human DNA primase‐polymerase required for the maintenance of genome integrity

Wan, Li; Lou, Jing; Xia, Yisui; Su, Bei; Liu, Ting; Cui, Jiamin; Sun, Yingying; Lou, Huiqiang; Huang, Jun

doi:10.1038/embor.2013.159

Cited by 173 publications

(249 citation statements)

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“…PrimPol has emerged as a DNA and RNA primase and DNAdependent translesion synthesis (TLS) polymerase (14)(15)(16)(17)(18). A 560-amino-acid protein belonging to the archaeo-eukaryotic primase (AEP) superfamily, PrimPol possesses a conserved N-terminal AEP polymerase domain with three highly conserved catalytic motifs and a C-terminal zinc finger domain similar to the viral UL52 primase domain (17,19).…”

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confidence: 99%

“…Investigational in vitro studies had identified that BMS-986094 was incorporated by the human mitochondrial RNA polymerase 30-fold more efficiently than ribavirin, the then-current standard of care, with "tolerable" off-target effects (13), highlighting the importance of understanding nucleoside analog incorporation by host polymerases to prevent life-threatening adverse events. Toward this end, the NRTI incorporation efficiencies have been determined for human B-, X-, and Y-family DNA polymerases (1) while the recent discovery of PrimPol operating in the nucleus and the mitochondria suggests an unexplored mechanism of NRTI-associated toxicity (14)(15)(16)(17).…”

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confidence: 99%

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Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol

Mislak

Anderson

2016

Antimicrob Agents Chemother

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Human PrimPol is a newly identified DNA and RNA primase-polymerase of the archaeo-eukaryotic primase (AEP) superfamily and only the second known polymerase in the mitochondria. Mechanistic studies have shown that interactions of the primary mitochondrial DNA polymerase ␥ (mtDNA Pol ␥) with nucleoside reverse transcriptase inhibitors (NRTIs), key components in treating HIV infection, are a major source of NRTI-associated toxicity. Understanding the interactions of host polymerases with antiviral and anticancer nucleoside analog therapies is critical for preventing life-threatening adverse events, particularly in AIDS patients who undergo lifelong treatment. Since PrimPol has only recently been discovered, the molecular mechanism of polymerization and incorporation of natural nucleotide and NRTI substrates, crucial for assessing the potential for PrimPolmediated NRTI-associated toxicity, has not been explored. We report for the first time a transient-kinetic analysis of polymerization for each nucleotide and NRTI substrate as catalyzed by PrimPol. These studies reveal that nucleotide selectivity limits chemical catalysis while the release of the elongated DNA product is the overall rate-limiting step. Remarkably, PrimPol incorporates four of the eight FDA-approved antiviral NRTIs with a kinetic profile distinct from that of mtDNA Pol ␥ that may manifest in toxicity.N ucleoside reverse transcriptase inhibitors (NRTIs) are an important class of antivirals that target the human immunodeficiency virus (HIV) polymerase, reverse transcriptase (RT). All FDA-approved NRTIs are nucleoside analogs that lack a 3=-hydroxyl moiety to terminate DNA chain extension upon incorporation by RT into the growing proviral DNA. While significant health advances have been achieved with the use of NRTIs, the necessity for lifelong treatment to control HIV infection is limited by NRTI-associated toxicities that arise from virus-versus-host polymerase selectivity wherein NRTIs also serve as substrates for host polymerases (1, 2).The most severe NRTI-associated toxicities predominantly manifest in mitochondrial dysfunction (1-6) and are attributed primarily to incorporation by the human mitochondrial DNA polymerase ␥ (mtDNA Pol ␥) (7-9). However, there are observed discrepancies between toxicity and the potential to inhibit mtDNA Pol ␥, suggesting alternative mechanisms and evaluation of additional host cell polymerases as potential perpetrators of antiviral toxicity (10, 11). Understanding the propensity for host cell polymerases to incorporate nucleoside analogs is critical for assessing safety in the design and development of antiviral, -parasitic, -bacterial, and -cancer nucleoside analog therapies. For instance, development of the antiviral ribonucleoside triphosphate analog BMS-986094 for the treatment of hepatitis C virus was halted in phase II after nine patients were hospitalized and one died (12). Investigational in vitro studies had identified that BMS-986094 was incorporated by the human mitochondrial RNA polymerase 30-fold more ...

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Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol

Mislak

Anderson

2016

Antimicrob Agents Chemother

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“…Recently, however, an additional DNA pol-primase, called PrimPol has been discovered. [140][141][142] The enzyme belongs to the archaea-eukaryotic primase superfamily. PrimPol activity is regulated by single stranded binding proteins and, differently from the DNA pol a/primase, can start DNA chains with desoxyribonucleotides.…”

Section: Primpolmentioning

confidence: 99%

History of DNA Polymerases

Maga¹,

Spadari²,

Villani³

et al. 2017

Human DNA Polymerases

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“…To identify novel factors playing important roles in the resolution of stalled replication forks, Wan and colleagues [1] used mass spectrometry to identify RPA-binding partners. Among the proteins identified were those already known to be located at replication forks, including SMARCAL1/HARP, BLM and TIMELESS.…”

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confidence: 99%