Geminin

1T6F, 1UII, 2LP0, 2WVR, 4BRY5105357441ENSG00000112312ENSMUSG00000006715O75496O88513NM_001251989NM_001251990NM_001251991NM_015895NM_020567NP_001238918NP_001238919NP_001238920NP_056979NP_065592Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene.1t6f: Crystal Structure of the Coiled-coil Dimerization Motif of Geminin1uii: Crystal structure of Geminin coiled-coil domain Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene. Geminin is a nuclear protein that is present in most eukaryotics and highly conserved across species. Numerous functions have been elucidated for Geminin including roles in metazoan cell cycle, cellular proliferation, cell lineage commitment, and neural differentiation. Geminin was originally identified as an inhibitor of DNA replication and substrate of the anaphase promoting complex (APC). Coincidentally, geminin was also shown to expand the neural plate in the developing Xenopus embryo. Geminin is a nuclear protein made up of about 200 amino acids, with a molecular weight of approximately 25 kDa. It contains an atypical leucine-zipper coiled-coil domain. It has no known enzymatic activity nor DNA binding motifs. Geminin is absent during G1 phase and accumulates through S, G2 phase and M phases of the cell cycle. Geminin levels drop at the metaphase / anaphase transition of mitosis when it is degraded by the Anaphase Promoting Complex (APC/C). During S phase, geminin is a negative regulator of DNA replication. In many cancer cell lines, inhibition of geminin by RNAi results in re-replication of portions of the genome, which leads to aneuploidy. In these cell lines, geminin knockdown leads to markedly slowed growth and apoptosis within several days. However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent DNA re-replication. Since geminin knockdown leads to cell death in many cancer cell lines but not primary cell lines, it has been proposed as a potential therapeutic target for cancer treatment. At the start of the S-phase until late mitosis, geminin inhibits the replication factor Cdt1, preventing the assembly of the pre-replicative complex. In early G1, the APC/C complex triggers its destruction through ubiquitination. Although inhibition of geminin by RNAi leads to impairment of DNA replication during the following cell cycle in many cancer cell lines, no such cell cycle defect is seen in primary and immortalized cell lines (although Cdt1 levels are still reduced in these cells).