p21WAF1/Cip1 acts as a key negative regulator of cell cycle progression, which can form complexes with cyclin-dependent kinases together with specific cyclins to induce cell cycle arrest at specific stages. p21 protein levels have been shown to be regulated primarily through phosphorylation and ubiquitination during various stages of the cell cycle. Although phosphorylation and ubiquitin-dependent proteasomal degradation of p21 have been well established, other post-translational modifications that contribute to regulation of p21 stability and function remain to be further elucidated. Here, we show that p21 degradation and its function are controlled by tankyrases, which are members of the poly(ADP-ribose) polymerase (PARP) protein family. p21 interacts with tankyrases via newly defined tankyrase-binding motifs and is PARylated by tankyrases in vitro and in vivo, suggesting that PARylation is a new post-translational modification of p21. Up-regulation of tankyrases induces ubiquitin-dependent proteasomal degradation of p21 through an E3 ligase RNF146, thus promoting cell cycle progression in the G1/S phase transition. On the contrary, inhibition of tankyrases by knockdown or inhibitor treatment stabilizes p21 protein and leads to cell cycle arrest in the G1 phase. Together, our data demonstrate that tankyrase may function as a new molecular regulator that controls the protein levels of p21 through PARylation-dependent proteasomal degradation. Hence, a novel function of the tankyrase-p21 axis may represent a new avenue for regulating cell cycle progression.
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Cover Image
Cover Image
Filamin A (FLNA) is a ubiquitously expressed actin-crosslinking protein that also serves as an intracellular signalling scaffold. In this issue De Silva and colleagues (pp. 2351–2364) used platelets from mice with a platelet-specific FLNA deficiency to test the role of FLNA in platelet apoptosis. Their data point to a novel role for FLNA in the regulation of platelet apoptosis. The cover image shows a schematic diagram illustrating part of a proposed model by which FLNA regulates ABT-induced caspase-3 cleavage. The image is courtesy of Hugh Kim.
Poly-ADP ribosylation of p21 by tankyrases promotes p21 degradation and regulates cell cycle progression
Misun Jung, Wonyoung Kim, Jin Won Cho, Won Ho Yang, In Kwon Chung; Poly-ADP ribosylation of p21 by tankyrases promotes p21 degradation and regulates cell cycle progression. Biochem J 30 November 2022; 479 (22): 2379–2394. doi: https://doi.org/10.1042/BCJ20220391
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