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

Landsverk, Helga B.; Sandquist, Lise Ellefsen; Sridhara, Sree Rama Chaitanya; Rødland, Gro Elise; Sabino, João C.; Almeida, Sérgio Fernandes de; Grallert, Beáta; Trinkle-Mulcahy, Laura; Syljuåsen, Randi G.

doi:10.1093/nar/gky1233

Cited by 13 publications

(28 citation statements)

References 77 publications

(100 reference statements)

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“…Indeed, our previous work on PNUTS-PP1 suggests that RNAPII pS5 promotes signaling via the apical DNA damage kinase, ataxia telangiectasia, and Rad3-related (ATR). 8 At first glance the connection between our previous and current findings seems obvious. ATR is well known to respond to replication stress, and therefore, T-R conflicts caused by RNAPII pS5 could be leading to ATR signaling.…”

supporting

confidence: 63%

“…Altogether, our results suggest that the phosphorylation status of the RNAPII CTD plays a key role in the regulation of both ATR activity 8 and replication stress 1 (Figure 1). In addition to its important roles in the regulation of transcription and mRNA processing, 10 the RNAPII CTD thus also appears to act as a signaling platform in genome maintenance.…”

mentioning

confidence: 59%

“…Interestingly, ATR activity after depletion of PNUTS was strongly reduced by co-depletion of cell division cycle 73 (CDC73), a phospho-CTD binding protein and component of the polymerase associated factor 1 (PAF1) transcription complex. 8 Furthermore, in our new work, we found that replication stress and RNAPII chromatin stability after depletion of PNUTS or its interacting partner WDR82 was also dependent on CDC73. 1 CDC73 may therefore contribute to ATR activity by stabilizing S5 phosphorylated RNAPII on chromatin.…”

mentioning

confidence: 62%

“…In addition, ATR signaling after depletion of PNUTS was higher than expected compared to similar levels of replication stress caused by hydroxyurea. 8 Furthermore, replication stress is believed to activate ATR by leading to single stranded DNA coated with replication protein A (RPA). 9 However, the high ATR signaling after depletion of PNUTS was not reduced by co-depletion of replication protein A 70 kDa DNA-binding subunit (RPA70), an essential subunit of the RPA complex.…”

mentioning

confidence: 99%

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New link between the RNA polymerase II-CTD and replication stress

Landsverk

Sandquist

Bay

et al. 2021

Molecular & Cellular Oncology

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supporting

confidence: 63%

mentioning

confidence: 59%

mentioning

confidence: 62%

mentioning

confidence: 99%

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New link between the RNA polymerase II-CTD and replication stress

Landsverk

Sandquist

Bay

et al. 2021

Molecular & Cellular Oncology

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“…Intriguingly, when TDR treatment was withdrawn, the cells were not fully arrested; rather, they progressed very slowly into S phase in the DOX+ group, as compared to the DOX-group ( Fig EV3A). The R-loop can also arrest the cell cycle in the G2/M phase by activating the cell-cycle checkpoint [19]. For that reason, we performed flow cytometry to detect the cell cycle to analyze the effects of the cell cycle under C1orf109L-eGFP expression.…”

Section: C1orf109l-egfp Influences the Cell-cycle G1/s Phase Transformentioning

confidence: 99%

C1orf109L promote R-loop accumulation induced DNA damage to inhibit cell growth

Dou

Xie

et al. 2019

Preprint

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As a function unknown gene, C1orf109 is lower expression in various cells. Here, we reported that C1orf109L, the longest variant of C1orf109, which interacted with R-loop-regulating proteins to trigger R-loop, a three-stranded nucleic acid structure frequently mediated genome instability, accumulation. C1orf109L induce chronic DNA damage to promote P21 upregulation and strongly inhibits cell growth in vitro and in vivo by arresting the cell cycle in the G2 phase. With camptothecin (CPT), an R-loop activator, treatment, C1orf109L further triggers R-loop accumulation-induced DNA damage and promotes cell death by activating cell-death pathway. Furthermore, CPT treatment increases C1orf109L ubiquitination and turnover, which inhibits cell death and promotes the G0/G1 phase of the cell cycle. Therefore, our data illustrated the mechanisms underlying C1orf109L-related cell growth inhibition and provide feasibility and limitations for C1orf109L as a potential target for cancer therapy. Cell proliferation depends on the cell cycle. In abnormal cells, such as benign tumor cells and cancer cells, cell-cycle dis-regulation promotes cell growth [1]. For the cancer therapy strategies are mainly to kill cancer cell or inhibit cancer cell growth. Inducing cancer cell DNA damage is an efficient way to induce cancer cell death or growth inhibition. When genomic DNA is damaged, many pathways involved in cell-cycle regulation are activated, the most important of which involves activation of the DNA-damage checkpoint to arrest the cell cycle at different stages, including G1, S, and G2/M, which ensures that the damaged cell has enough time to repair DNA damage [2,3]. If DNA damage is so severe or the rate of damage is faster than the rate of the repairing process, then the cellular-death pathway is activated [4]. Among the DNA-damage checkpoints, the G1 and G2/M checkpoint restricts mitosis onset in response to multiple exogenous and endogenous factors [5]. With respect to endogenous factors, several proteins act as RNA-processing regulators that control the cell's fate, while dysfunction of RNA-processing-related proteins could trigger R-loop accumulation, and RNA-DNA hybrids can lead to DNA damage and induce-cell cycle arrest, which is an important factor for genome instability in abnormal cells, especially in cancer cells [6,7]. The R-loop also controls gene expression [8] and immunoglobulin (Ig)G class switching [9]. However, the regulation of R-loop proteins is poorly explored. Thus, in this study, we identified the novel gene, c1orf109, which is downregulated in a variety of cell lines. C1orf109L-eGFP expression triggers R-loop accumulation to induce DNA damage and arrest the cell cycle. We report that C1orf109L interacted with R-loop associated proteins and located on R-loops. C1orf109L overexpression that triggered R-loop accumulation no matter with or without CPT treatment in cells. The accumulated R-loops induced DNA damage which inhibits cell growth in vitro and in vivo. In terms of the mechanism underlying cell growth, t...

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