TIP60 recruits SUV39H1 to chromatin to maintain heterochromatin genome stability and resist hydrogen peroxide-induced cytotoxicity

Tat interacting protein 60 (TIP60) is a histone acetyltransferase involved in chromatin remodeling and the DNA damage response. However, the role of TIP60 in maintaining genome stability is poorly understood. Here, we show that TIP60 can directly interact with suppressor of variegation 3–9 homologue 1 (SUV39H1), a methyltransferase that is responsible for histone H3 tri-methylation on Lys9 (H3K9me3). When we knocked down TIP60 or treated cells with hydrogen peroxide, a typical reactive oxygen species (ROS) generator that induces genome instability, SUV39H1 dissociated from chromatin but its acetylation levels remained unchanged. Consequently, H3K9me3 levels in the heterochromatin decreased, leading to a significant increase in the expression of satellite 2 (Sat2) and α-satellite (α-Sat), indicators of heterochromatin relaxation. Micrococcal nuclease sensitivity and colony formation assays further demonstrated that TIP60 knockdown or hydrogen peroxide treatment resulted in a relaxing of the heterochromatin and genome instability. Exogenous TIP60 could rescue the assembly of SUV39H1 on chromatin and ensure genome stability in response to hydrogen peroxide. This study is the first to describe a role for TIP60 in maintaining heterochromatin structure and genome stability by recruiting SUV39H1 to the chromatin upon oxidative stress, presenting TIP60 as a promising target to sensitize cancer cells to ROS-promoting therapies.