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PARP14 regulates cyclin D1 expression to promote cell-cycle progression

Oncogene volume 40, pages 4872–4883 (2021)Cite this article

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Abstract

Cyclin D1 is an essential regulator of the G1–S cell-cycle transition and is overexpressed in many cancers. Expression of cyclin D1 is under tight cellular regulation that is controlled by many signaling pathways. Here we report that PARP14, a member of the poly(ADP-ribose) polymerase (PARP) family, is a regulator of cyclin D1 expression. Depletion of PARP14 leads to decreased cyclin D1 protein levels. In cells with a functional retinoblastoma (RB) protein pathway, this results in G1 cell-cycle arrest and reduced proliferation. Mechanistically, we found that PARP14 controls cyclin D1 mRNA levels. Using luciferase assays, we show that PARP14 specifically regulates cyclin D1 3′UTR mRNA stability. Finally, we also provide evidence that G1 arrest in PARP14-depleted cells is dependent on an intact p53–p21 pathway. Our work uncovers a new role for PARP14 in promoting cell-cycle progression through both cyclin D1 and the p53 pathway.

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Fig. 1: PARP14 is required for cell-cycle progression.
Fig. 2: PARP14 is required for RB phosphorylation and E2F1 target protein expression.
Fig. 3: Cell-cycle arrest due to PARP14 knockdown is not observed in RPE-1 RB/p107/p130 triple knockout cells or HeLa cells.
Fig. 4: Depletion of p21 or p53 moderately rescues cell-cycle arrest caused by PARP14 knockdown.
Fig. 5: PARP14 regulates Cyclin D1 protein expression and mRNA levels.
Fig. 6: Overexpression of Cyclin D1 rescues both the E2F1 protein expression and the CDK4/6 kinase activity defects caused by PARP14 knockdown.
Fig. 7: PARP14 is required for Cyclin D1 3′UTR mRNA stability.

Data availability

All source data underlying each figure, including the values plotted in graphs, the exact p values, and the uncropped blots are presented in Supplementary Table S1.

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Acknowledgements

We would like to thank Drs James Broach, Gregory Yochum, Lisa Shantz, Hein Te Riele, Titia de Lange, Nicholas Dyson, Hong-Gang Wang, Raymond Hohl, Myriam Gorospe, Khandan Keyomarsi, and Peter Sicinski for materials and advice, as well as the Penn State College of Medicine Flow Cytometry core for their assistance with flow cytometry experiments. This work was supported by NIH R01ES026184 (to G-LM).

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  1. Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    Michael J. O’Connor, Tanay Thakar, Claudia M. Nicolae & George-Lucian Moldovan

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Correspondence to George-Lucian Moldovan.

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O’Connor, M.J., Thakar, T., Nicolae, C.M. et al. PARP14 regulates cyclin D1 expression to promote cell-cycle progression. Oncogene 40, 4872–4883 (2021). https://doi.org/10.1038/s41388-021-01881-8

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