4oa7
Crystal structure of Tankyrase1 in complex with IWR1
Structural highlights
FunctionTNKS1_HUMAN Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedMaintenance of chromosomal ends (telomeres) directly contributes to cancer cell immortalization. The telomere protection enzymes belonging to the Tankyrase (Tnks) subfamily of PARPs have recently been shown to also control transcriptional response to secreted Wnt signaling molecules. Whereas Tnks inhibitors are currently being developed as therapeutic agents for targeting Wnt-related cancers and as modulators of Wnt signaling in tissue engineering agendas, their impact on telomere length maintenance remains unclear. Here, we have leveraged a collection of Wnt pathway inhibitors with previously unassigned mechanisms of action to identify novel pharmacophores supporting Tnks inhibition. A multifaceted experimental approach that includes structural, biochemical, and cell biological analyses reveals two distinct chemotypes with selectivity for Tnks enzymes. Using these reagents, we reveal Tnks inhibition rapidly induces DNA damage at telomeres and telomeric shortening upon long-term chemical exposure in cultured cells. On the other hand, inhibitors of the Wnt acyltransferase Porcupine (Porcn) elicited neither effect. Thus, Tnks inhibitors impact telomere length maintenance independently of their affects on Wnt/beta-catenin signaling. We discuss the implications of these findings for anti-cancer and regenerative medicine agendas dependent upon chemical inhibitors of Wnt/beta-catenin signaling. Disruption of Wnt/beta-catenin signaling and telomeric shortening are inextricable consequences of tankyrase inhibition in human cells.,Kulak O, Chen H, Holohan B, Wu X, He H, Borek D, Otwinowski Z, Yamaguchi K, Garofalo LA, Ma Z, Wright W, Chen C, Shay JW, Zhang X, Lum L Mol Cell Biol. 2015 May 4. pii: MCB.00392-15. PMID:25939383[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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