ATR Restrains DNA Synthesis and Mitotic Catastrophe in Response to CDC7 Inhibition

Rainey, Michael D.; Bennett, Declan; O’Dea, Rachel; Zanchetta, Melania Eva; Voisin, Muriel; Seoighe, Cathal; Santocanale, Corrado

doi:10.1016/j.celrep.2020.108096

Cited by 36 publications

(41 citation statements)

References 86 publications

(141 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of replication tracts showed that cATRi drastically reduces fork elongation rate in U-2OS and HCT116 cells (Figure 1B). Consistent with previous reports showing a role for ATR in repressing origin firing (Buisson et al, 2015;Couch et al, 2013;Moiseeva et al, 2017Moiseeva et al, , 2019Mutreja et al, 2018;Rainey et al, 2020), we found that fork speed was rescued by CDC7 inhibition (Figure 1C). Increased origin firing upon acute ATRi is thought to generate DNA breaks and replication catastrophe in response to HU or aphidicolin (Couch et al, 2013;Toledo et al, 2013).…”

Section: Catri Uncouples Origin Firing and Fork Speed From Genomic Instabilitysupporting

confidence: 93%

“…Consistently, Neutral Comet assay results showed chromosome fragmentation in cells after ionizing radiation but not upon cATRi (Figure 1E). Moreover, we directly compared DSB signaling markers in cells following either cATRi or acute ATRi (aATRi), selecting a AZD6738 dose that was recently used to show a role of ATR in origin firing regulation (Moiseeva et al, 2019;Rainey et al, 2020). Consistent with our results showing the lack of extensive breaks upon cATRi, the signaling response induced by cATRi was markedly different from the response induced by aATRi, which confirmed the expected effect of aATRi in causing DSBs (Figure 1F) (Buisson et al, 2015).…”

Section: Catri Uncouples Origin Firing and Fork Speed From Genomic Instabilitysupporting

confidence: 81%

See 1 more Smart Citation

Fork Slowing and Reversal as an Adaptive Response to Chronic ATR Inhibition

Dibitetto

Sanchi

Sanford

et al. 2021

Preprint

View full text Add to dashboard Cite

Inhibitors of the replication stress response kinase ATR are currently being explored in anti-cancer therapy. Acute ATR inhibition is known to impair the proper control of origin firing, DNA repair, and cell cycle, resulting in DNA breaks and mitotic catastrophe. Less is understood about the effects of clinically relevant regimes of ATR inhibition, which involve chronic and low doses of ATR inhibitors (cATRi) to cells. Here we report distinctive molecular effects of cATRi on replication dynamics. cATRi strongly reduces fork speed but has minimal effects on the accumulation of DNA breaks or cell survival. cATRi promotes extensive fork reversal and RAD51- and PARP-mediated fork slowing that correlate with the accumulation of DNA-RNA hybrids. Our work shows that fork reversal is a critical adaptive response ensuring cell survival during cATRi and that the manipulation of fork reversal causes hypersensitivity to cATRi, increasing the effectiveness of ATR inhibitors in anti-cancer therapies.

show abstract

Section: Catri Uncouples Origin Firing and Fork Speed From Genomic Instabilitysupporting

confidence: 93%

Section: Catri Uncouples Origin Firing and Fork Speed From Genomic Instabilitysupporting

confidence: 81%

Fork Slowing and Reversal as an Adaptive Response to Chronic ATR Inhibition

Dibitetto

Sanchi

Sanford

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…This targets PP1 to pre-RC phospho-sites, acting both negatively on origin activation by counteracting the phosphorylation of MCM by DDK ( 15–17 ), and positively on the licensing step ( 18 ). In metazoans, Rif1 also modulates cellular responses and suppresses DNA replication after the inhibition of Cdc7 ( 19 ), and Rif1 bound to the nuclear lamina regulates replication firing time as a possible organiser of chromatin architecture ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Polo-like kinase 1 (Plk1) regulates DNA replication origin firing and interacts with Rif1 in Xenopus

Ciardo

Haccard

Narassimprakash

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

The activation of eukaryotic DNA replication origins needs to be strictly controlled at multiple steps in order to faithfully duplicate the genome and to maintain its stability. How the checkpoint recovery and adaptation protein Polo-like kinase 1 (Plk1) regulates the firing of replication origins during non-challenged S phase remained an open question. Using DNA fiber analysis, we show that immunodepletion of Plk1 in the Xenopus in vitro system decreases replication fork density and initiation frequency. Numerical analyses suggest that Plk1 reduces the overall probability and synchrony of origin firing. We used quantitative chromatin proteomics and co-immunoprecipitations to demonstrate that Plk1 interacts with firing factors MTBP/Treslin/TopBP1 as well as with Rif1, a known regulator of replication timing. Phosphopeptide analysis by LC/MS/MS shows that the C-terminal domain of Rif1, which is necessary for its repressive action on origins through protein phosphatase 1 (PP1), can be phosphorylated in vitro by Plk1 on S2058 in its PP1 binding site. The phosphomimetic S2058D mutant interrupts the Rif1-PP1 interaction and modulates DNA replication. Collectively, our study provides molecular insights into how Plk1 regulates the spatio-temporal replication program and suggests that Plk1 controls origin activation at the level of large chromatin domains in vertebrates.

show abstract

“…Anomalous mitotic entry before the completion of DNA replication may result in mitotic catastrophe and is correlated with multipolar spindle and giant, multinuclear cells. 39 In addition, mitotic catastrophe is a non-lethal process, but it includes a crossroad that might drive cells into necrosis or apoptosis, 40 and the inhibition of apoptosis may mitigate asymmetrical division and the aneuploid cell generation. 41 Our study indicated that the increased apoptotic rate of HG-treated cells was an outcome of both podocyte injury and mitotic catastrophe.…”

Section: Discussionmentioning

confidence: 99%