Abstract 5092: Geminin regulates pre-replicative complex formation through the stabilization of CDT1 in mitosis

Abstract

Abstract Geminin, a factor essential to DNA replication, directly binds to the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation to avoid re-replication. Geminin protein expression is necessary during S, G2 and M phases of the cell cycle. In G1, geminin levels are kept in check by the anaphase-promoting complex/cyclosome ubiquitin ligase complex and its activator (APC/CCdh1), which targets geminin for proteasomal degradation to allow pre-RC formation. Conversely, from S to G2 is stabilized by the APC/C inhibitor Emi1 to ensure inhibition of Pre-RC formation. In this study, we found that Aurora-A phosphorylated geminin at Thr25 in M phase and the Aurora-A-mediated phosphorylation stabilized geminin by preventing its degradation via APC/C during mitosis. Aurora-A-mediated stabilization of geminin may further give rise to that of CDT1 protein to ensure pre-RC formation in the ensuing S phase. The Aurora-A-geminin-CDT1 axis, thus, represents a critical function for regulating proper DNA replication. Citation Format: Yasusei Kudo, Takaaki Tsunematsu, Naozumi Ishimaru. Geminin regulates pre-replicative complex formation through the stabilization of CDT1 in mitosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5092. doi:10.1158/1538-7445.AM2014-5092