PrimPol breaks replication barriers

Helleday, Thomas

doi:10.1038/nsmb.2727

Cited by 17 publications

(8 citation statements)

References 20 publications

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“…Besides SLFN11, RPA interacts with a large number of proteins involved in DNA replication, cell cycle regulation, and DNA repair and has been considered as a platform that promotes critical biochemical reactions that occur at ssDNA. For example, we and several other groups have demonstrated that hPrimpol1/CCDC111/Primpol , the PSO4/PRP19 complex , HARP/SMARCAL1 , and several other proteins possessing enzymatic activities can be recruited to sites of DNA damage through the direct interaction with RPA. While SLFN11 inhibits checkpoint maintenance and HR repair, almost all the known RPA‐binding proteins positively regulate DNA damage response.…”

Section: Discussionmentioning

confidence: 96%

SLFN 11 inhibits checkpoint maintenance and homologous recombination repair

et al. 2015

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High expression levels of SLFN11 correlate with the sensitivity of human cancer cells to DNA-damaging agents. However, little is known about the underlying mechanism. Here, we show that SLFN11 interacts directly with RPA1 and is recruited to sites of DNA damage in an RPA1-dependent manner. Furthermore, we establish that SLFN11 inhibits checkpoint maintenance and homologous recombination repair by promoting the destabilization of the RPA-ssDNA complex, thereby sensitizing cancer cell lines expressing high endogenous levels of SLFN11 to DNA-damaging agents. Finally, we demonstrate that the RPA1-binding ability of SLFN11 is required for its function in the DNA damage response. Our findings not only provide novel insight into the molecular mechanisms underlying the drug sensitivity of cancer cell lines expressing SLFN11 at high levels, but also suggest that SLFN11 expression can serve as a biomarker to predict responses to DNAdamaging therapeutic agents.

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Section: Discussionmentioning

confidence: 96%

SLFN 11 inhibits checkpoint maintenance and homologous recombination repair

et al. 2015

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“…Also, CHK1 phosphorylation was induced by UV damage when recombinant PCNA K164R mutant that cannot be monoubiquitylated, and not wild-type (WT) PCNA, was added to extracts at a low N/C ratio ( Figure S2H). Of note, the recently discovered PRIMPOL (see Helleday, 2013, for a review), was not bound to chromatin at a low N/C ratio ( Figure S2I), ruling out active UV lesions bypass or replication fork restart by this polymerase. Finally, (D) CHK1 phosphorylation analyzed by western blot in either mock-depleted or RAD18-depleted egg extracts with UV-irradiated (+UV) or not (ÀUV) sperm nuclei at a low N/C ratio as well as with recombinant ( Rec ) His 6 -RAD6-RAD18.…”

Section: Rad6-rad18 Inhibits the Uv-dependent Dna Damagementioning

confidence: 97%

RAD18 Is a Maternal Limiting Factor Silencing the UV-Dependent DNA Damage Checkpoint in Xenopus Embryos

et al. 2015

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In early embryos, the DNA damage checkpoint is silent until the midblastula transition (MBT) because of maternal limiting factors of unknown identity. Here we identify the RAD18 ubiquitin ligase as one such factor in Xenopus. We show, in vitro and in vivo, that inactivation of RAD18 function leads to DNA damage-dependent checkpoint activation, monitored by CHK1 phosphorylation. Moreover, we show that the abundance of both RAD18 and PCNA monoubiquitylated (mUb) are developmentally regulated. Increased DNA abundance limits the availability of RAD18 close to the MBT, thereby reducing PCNA(mUb) and inducing checkpoint derepression. Furthermore, we show that this embryonic-like regulation can be reactivated in somatic mammalian cells by ectopic RAD18 expression, therefore conferring resistance to DNA damage. Finally, we find high RAD18 expression in cancer stem cells highly resistant to DNA damage. Together, these data propose RAD18 as a critical embryonic checkpoint-inhibiting factor and suggest that RAD18 deregulation may have unexpected oncogenic potential.

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“…These enzymes belong to a large functionally diverse superfamily of ancient enzymes equipped with broad enzymatic capabilities related to DNA metabolism and are present in all domains of life. There is a great deal of evidence suggesting that among a large variety of cellular functions fulfilled by PrimPols a very prominent role is that of TLS past various replicase stalling lesions [recently reviewed in (Guilliam et al , 2015; Helleday, 2013)].…”

Section: Historic Overviewmentioning

confidence: 99%

Translesion DNA polymerases in eukaryotes: what makes them tick?

Vaisman

Woodgate

2017

Critical Reviews in Biochemistry and Molecular Biology

214

204

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Life as we know it, simply would not exist without DNA replication. All living organisms utilize a complex machinery to duplicate their genomes and the central role in this machinery belongs to replicative DNA polymerases, enzymes that are specifically designed to copy DNA. “Hassle-free” DNA duplication exists only in an ideal world, while in real life, it is constantly threatened by a myriad of diverse challenges. Among the most pressing obstacles that replicative polymerases often cannot overcome by themselves, are lesions that distort the structure of DNA. Despite elaborate systems that cells utilize to cleanse their genomes of damaged DNA, repair is often incomplete. The persistence of DNA lesions obstructing the cellular replicases can have deleterious consequences. One of the mechanisms allowing cells to complete replication is “Translesion DNA Synthesis (TLS). TLS is intrinsically error-prone, but apparently, the potential downside of increased mutagenesis is a healthier outcome for the cell than incomplete replication. Although most of the currently identified eukaryotic DNA polymerases have been implicated in TLS, the best characterized are those belonging to the “Y-family” of DNA polymerases (pols η, ι, κ, and Rev1), which are thought to play major roles in the TLS of persisting DNA lesions in coordination with the B-family polymerase, pol ζ. In this review, we summarize the unique features of these DNA polymerases by mainly focusing on their biochemical and structural characteristics, as well as potential protein-protein interactions with other critical factors affecting TLS regulation.

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PrimPol breaks replication barriers

Cited by 17 publications

References 20 publications

SLFN 11 inhibits checkpoint maintenance and homologous recombination repair

SLFN 11 inhibits checkpoint maintenance and homologous recombination repair

RAD18 Is a Maternal Limiting Factor Silencing the UV-Dependent DNA Damage Checkpoint in Xenopus Embryos

Translesion DNA polymerases in eukaryotes: what makes them tick?

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