A novel role for ATR/Rad3 in G1 phase

Bøe, Cathrine Arnason; Håland, Tine Weise; Boye, Erik; Syljuåsen, Randi G.; Grallert, Beáta

doi:10.1038/s41598-018-25238-6

Cited by 9 publications

(5 citation statements)

References 53 publications

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“…Interestingly, previous studies have suggested that blockage of elongating RNAPII is sufficient to induce ATR signaling in human cells (7), and ATR has been shown to be activated in G1-phase (46,47), when replication does not occur. We reasoned that signaling via phosphorylated RNAPII CTD might be a mechanism permitting ATR activation in G1.…”

Section: Resultsmentioning

confidence: 99%

Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1

Landsverk

Sandquist

Sridhara

et al. 2018

Nucleic Acids Research

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Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is a key factor activated by DNA damage and replication stress. An alternative pathway for ATR activation has been proposed to occur via stalled RNA polymerase II (RNAPII). However, how RNAPII might signal to activate ATR remains unknown. Here, we show that ATR signaling is increased after depletion of the RNAPII phosphatase PNUTS-PP1, which dephosphorylates RNAPII in its carboxy-terminal domain (CTD). High ATR signaling was observed in the absence and presence of ionizing radiation, replication stress and even in G1, but did not correlate with DNA damage or RPA chromatin loading. R-loops were enhanced, but overexpression of EGFP-RNaseH1 only slightly reduced ATR signaling after PNUTS depletion. However, CDC73, which interacted with RNAPII in a phospho-CTD dependent manner, was required for the high ATR signaling, R-loop formation and for activation of the endogenous G2 checkpoint after depletion of PNUTS. In addition, ATR, RNAPII and CDC73 co-immunoprecipitated. Our results suggest a novel pathway involving RNAPII, CDC73 and PNUTS-PP1 in ATR signaling and give new insight into the diverse functions of ATR.

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Section: Resultsmentioning

confidence: 99%

Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1

Landsverk

Sandquist

Sridhara

et al. 2018

Nucleic Acids Research

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“…40 ). Despite this well-established model, evidence for ATR activation in G1phase cells has been recently presented 41,42 . We report here that repression of Pol I transcription and nucleolar segregation are dependent on ATR activity throughout the cell cycle, even in G1 phase, when no sister chromatids are present, and resection of broken rDNA does not take place.…”

Section: Discussionmentioning

confidence: 99%

Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

et al. 2020

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Induction of DNA double-strand breaks (DSBs) in ribosomal DNA (rDNA) repeats is associated with ATM-dependent repression of ribosomal RNA synthesis and large-scale reorganization of nucleolar architecture, but the signaling events that regulate these responses are largely elusive. Here we show that the nucleolar response to rDNA breaks is dependent on both ATM and ATR activity. We further demonstrate that ATM-and NBS1-dependent recruitment of TOPBP1 in the nucleoli is required for inhibition of ribosomal RNA synthesis and nucleolar segregation in response to rDNA breaks. Mechanistically, TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of the nucleolar phosphoprotein Treacle. Our data thus reveal an important cooperation between TOPBP1 and Treacle in the signaling cascade that triggers transcriptional inhibition and nucleolar segregation in response to rDNA breaks.

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“…The dCK exists in phosphorylated form under basic conditions because it is constitutively active in cells responsible for the phosphorylation of Ser-74. ATR regulates dCK activity not only in cells with damaged DNA, but also in normal cells and in hematopoietic or epithelial cancer cells 28 . CLA significantly increased the level of ATR and ATM mRNA, which played an important role in dCK kinase phosphorylation 10 .…”

Section: Discussionmentioning

confidence: 99%

Antileukemic activity of novel adenosine derivatives

Poczta

Rogalska

Łukawska

et al. 2019

Sci Rep

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The present study investigated the effect of cladribine (CLA) and six of its derivatives containing a formamidine group at position 6 (CLA-FDM, CLA-FPAZ, CLA-FPIR, CLA-FPIP, CLA-FHEX, and CLA-FMOR) on acute promyelocytic, lymphoblastic, and acute monocytic leukemia cells. The role of ATR kinase in deoxycytidine kinase (dCK) activation in response to DNA damage was assessed. The presence of DNA lesions was assessed by measurement phosphorylation of H2AX and by using the alkaline comet assay with proteinase K post-treatment following assessment of the cell cycle. Apoptotic events such as alterations in intracellular calcium concentration, caspase-3/7 activity and increased sub-G1 cell population were measured. CLA derivatives were highly effective against leukemic cells, showing high cytotoxicity, causing DNA fragmentation, and inducing DNA-protein cross-links in leukemic cells. CLA-FMOR showed the highest efficacy. CLA derivatives increased the levels of intracellular calcium ions, caspase-3/7 and the percentage of sub-G1 apoptotic cells and blocked cells in the S phase of the cell cycle to a greater extent than free CLA. The selective ATR inhibitor VE-821 significantly suppressed the increase in dCK activity and decreased basal dCK activity. The present results suggested that ATR kinase controls dCK activity in response to synthetic CLA derivatives.

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A novel role for ATR/Rad3 in G1 phase

Cited by 9 publications

References 53 publications

Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1

Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1

Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

Antileukemic activity of novel adenosine derivatives

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