Tankyrase 1 regulates centrosome function by controlling CPAP stability

Abstract

CPAP-a gene mutated in primary microcephaly-is required for procentriole formation. Here we show that CPAP degradation and function is controlled by the poly(ADP-ribose) polymerase tankyrase 1. CPAP is PARsylated by tankyrase 1 in vitro and in vivo. Overexpression of tankyrase 1 leads to CPAP proteasomal degradation, preventing centriole duplication, whereas depletion of tankyrase 1 stabilizes CPAP in G1, generating elongated procentrioles and multipolarity. Tankyrase 1 localizes to centrosomes exclusively in G1, coinciding with CPAP degradation. Hence, tankyrase 1-mediated PARsylation regulates CPAP levels during the cell cycle to limit centriole elongation and ensure normal centrosome function.

Centrobin-mediated Regulation of the Centrosomal Protein 4.1-associated Protein (CPAP) Level Limits Centriole Length during Elongation Stage

“…Our results show that in comparison with untreated cells, a significant accumulation of CPAP occurs in MG-132-treated control shRNA cells (Fig. 4A), reiterating earlier observations that CPAP is proteasomally degraded (39,43). Importantly, although CPAP was significantly down-regulated in untreated centrobin-depleted cells, MG-132 treatment did restore the CPAP expression in them, albeit not equivalent to the levels of MG-132-treated control cells.…”

“…Inhibition of the Proteasome Pathway Restores Cellular CPAP Levels in Centrobin-depleted Cells-CPAP is degraded by the proteasome in late mitotic/early G 1 cells (39,43). However, what triggers CPAP degradation and termination of centriole elongation at this phase is not known.…”

“…CPAP is ubiquitinated and degraded by the proteasome during mitosis (39,43). Interestingly, the elongation phase of centriole duplication, which determines centriole length, is completed by the time cells reach mitosis (44).…”

Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

“…2G). Since ribosylation of some tankyrase substrates is known to lead to their degradation via a proteasome-dependent pathway (Huang et al 2009;Kim et al 2011;Levaot et al 2011), we decided to test whether tankyrases could affect PTEN ubiquitination and degradation.…”

“…Tankyrase1 (TNKS1)/PARP5a and TNKS2/PARP5b are members of the poly(ADP-ribose) polymerase (PARP) family and are known to have diverse functions (Smith et al 1998;Ye and de Lange 2004;Kim et al 2011;Ozaki et al 2012). Tankyrase-induced ribosylation of TRF1 Ó 2015 Li et al This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml).…”