Gadd45a is a p53-regulated gene whose protein product, like p53, is involved in maintenance of genome stability. Specifically, deletion of Gadd45a leads to extensive aneuploidy as a consequence of centrosome amplification and subsequent abnormal segregation of chromosomes during mitosis. S-phase checkpoints were investigated in Gadd45a-/- cells to determine possible defects contributing to the uncoupling of centrosome duplication and DNA replication. In the presence of hydroxyurea, Gadd45a-/- mouse embryo fibroblasts show increased centrosome amplification coupled with loss of a sustained S-phase checkpoint. Gadd45a deletion allows another form of genomic instability, gene amplification, when p21 (Cdkn1a gene product) is deleted also. Gene amplification in Gadd45a-/-p21-/- cells correlated with loss of both G1 and S-phase checkpoints. Multiple conditions of nutrient deprivation failed to prevent DNA synthesis in Gadd45a-/- cells. Gadd45a is therefore required for proper S-phase control and checkpoints under multiple conditions of nutrient deprivation. It is proposed that loss of S-phase control may account for both the uncoupling of DNA replication and centrosome duplication, and conferring gene amplification proficiency in cells lacking Gadd45a-/-. This is of particular importance for solid tumors, which may lack sufficient nutrients yet are unable to elicit checkpoints preventing genomic instability under these conditions.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Developmental Biology
- Cell Biology