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

Abstract

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.

SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair

“…Initially recognised as a protein of 60 kDa, TIP60, also referred to as KAT5, is a member of the MYST family of HATs (histone acetyltransferases), which is linked to the HIV Tat 28 . TIP60 participates in multiple cellular processes, such as chromatin reconstruction, gene transcription, apoptosis, maintain genomic stability 29 and DNA repair 30 . Once DNA double strands break occurs, TIP60 localises itself on the damaged sites and acetylates H3, H4 and γH2AX, leading to chromatin relaxation and remodelling 31–34 .…”

Biological function and regulation of histone 4 lysine 20 methylation in DNA damage response

“…KMT1A (SUV39H1) is a methyltransferase of H3K9 methylation and is linked to the organization of higher-order chromatin and the recruitment of HP1 to DSBs (Ayrapetov et al, 2014;Rea et al, 2000;Tu et al, 2020). KMT1B (SUV39H2) is a methyltransferase of H2AXK134me2 (Sone et al, 2014), which regulates γ-H2AX levels during the DDR (Sone et al, 2014).…”