An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis.
There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.
Pubmed ID: 20154723 RIS Download
Acetylation | Animals | Binding Sites | Cell Division | Chromosome Fragile Sites | Cyclin-Dependent Kinase Inhibitor p21 | DNA Damage | G2 Phase | Histone Deacetylase 1 | Humans | Mice | NIH 3T3 Cells | Neoplasms, Radiation-Induced | Tumor Suppressor Proteins | Ubiquitination