Loss of Geminin induces rereplication in the presence of functional p53.

TY - JOUR

T1 - Loss of Geminin induces rereplication in the presence of functional p53.

AU - Melixetian, Marina

AU - Ballabeni, Andrea

AU - Masiero, Laura

AU - Gasparini, Patrizia

AU - Zamponi, Raffaella

AU - Bartek, Jiri

AU - Lukas, Jiri

AU - Helin, Kristian

N1 - Keywords: Cell Cycle; Cell Cycle Proteins; Cell Death; Cell Line, Tumor; Cell Nucleus; Cell Transformation, Neoplastic; DNA Replication; DNA-Binding Proteins; Genes, cdc; Genomic Instability; Histones; Humans; Mitosis; Nuclear Proteins; Polyploidy; Protein Kinases; Rad51 Recombinase; Tumor Suppressor Protein p53

PY - 2004

Y1 - 2004

N2 - Strict regulation of DNA replication is essential to ensure proper duplication and segregation of chromosomes during the cell cycle, as its deregulation can lead to genomic instability and cancer. Thus, eukaryotic organisms have evolved multiple mechanisms to restrict DNA replication to once per cell cycle. Here, we show that inactivation of Geminin, an inhibitor of origin licensing, leads to rereplication in human normal and tumor cells within the same cell cycle. We found a CHK1-dependent checkpoint to be activated in rereplicating cells accompanied by formation of gammaH2AX and RAD51 nuclear foci. Abrogation of the checkpoint leads to abortive mitosis and death of rereplicated cells. In addition, we demonstrate that the induction of rereplication is dependent on the replication initiation factors CDT1 and CDC6, and independent of the functional status of p53. These data show that Geminin is required for maintaining genomic stability in human cells.

AB - Strict regulation of DNA replication is essential to ensure proper duplication and segregation of chromosomes during the cell cycle, as its deregulation can lead to genomic instability and cancer. Thus, eukaryotic organisms have evolved multiple mechanisms to restrict DNA replication to once per cell cycle. Here, we show that inactivation of Geminin, an inhibitor of origin licensing, leads to rereplication in human normal and tumor cells within the same cell cycle. We found a CHK1-dependent checkpoint to be activated in rereplicating cells accompanied by formation of gammaH2AX and RAD51 nuclear foci. Abrogation of the checkpoint leads to abortive mitosis and death of rereplicated cells. In addition, we demonstrate that the induction of rereplication is dependent on the replication initiation factors CDT1 and CDC6, and independent of the functional status of p53. These data show that Geminin is required for maintaining genomic stability in human cells.

U2 - 10.1083/jcb.200403106

DO - 10.1083/jcb.200403106

M3 - Journal article

C2 - 15159417

SN - 0021-9525

VL - 165

SP - 473

EP - 482

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 4

ER -