SIRT1 deacetylates TopBP1 and modulates intra-S-phase checkpoint and DNA replication origin firing.

摘要: SIRT1, the mammalian homolog of yeast Sir2, is a founding member family 7 protein and histone deacetylases that are involved in numerous biological functions. Previous studies revealed SIRT1 deficiency results genome instability, which eventually leads to cancer formation, yet underlying mechanism unclear. To investigate this, we conducted proteomics study found interacted with many proteins replication fork protection origin firing. We demonstrated loss resulted increased firing, asymmetric progression, defective intra-S-phase checkpoint, chromosome damage. Mechanistically, deacetylates affects activity TopBP1, plays an essential role DNA Our ectopic over-expression deacetylated form TopBP1 mutant cells repressed while acetylated lost this function. Thus, acts upstream maintaining stability by modulating initiation cell cycle checkpoint.