Tip60: updates

Abstract

The maintenance of genome integrity is essential for organism survival. Therefore, eukaryotic cells possess many DNA repair mechanisms in response to DNA damage. Acetyltransferase, Tip60, plays a central role in ATM and p53 activation which are involved in DNA repair. Recent works uncovered the roles of Tip60 in ATM and p53 activation and how Tip60 is recruited to double-strand break sites. Moreover, recent works have demonstrated the role of Tip60 in cancer progression. Here, we review the current understanding of how Tip60 activates both ATM and p53 in response to DNA damage and his new roles in tumorigenesis.

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

“…TIP60 also interacts with various non-histone substrates, including aurora-B, p53 and ataxia telangiectasia mutated (ATM), to catalyze Bo Tu, Yantao Bao and Ming Tang contributed equally to this work. their acetylation (Ghobashi and Kamel 2018;Li et al 2020;Mo et al 2016;Sun et al 2005;Tang et al 2006). Unsurprisingly, TIP60 is closely associated with gene expression, DNA damage repair and tumor development (Kim et al 2019), and its function is likely dependent on its enzymatic activity.…”

“…For example, in response to severe genotoxic stress, TIP60 can cooperate with multiple proteins, including p53 (Liu et al 2019;Tang et al 2006;Yang et al 2020), programmed cell death 5 (PDCD5) (Li et al 2016), or axin (Li et al 2009), to induce apoptosis. In response to reparable DNA damage, TIP60 activates proteins including H4 (Tang et al 2013), ATM (Ghobashi and Kamel 2018;Sun et al 2005) and the ribonucleotide reductase catalytic subunit M1 (RRM1) (Niida et al 2010) to arrest the cell cycle, recruit the DNA damage repair complex and facilitate cell survival. In this way, TIP60 has a dynamic role in protecting DNA from damage and maintaining genome stability during the DNA damage response (DDR).…”

MYC in Germinal Center‐derived lymphomas: Mechanisms and therapeutic opportunities

“…While likely to contribute to MYC‐dependent histone acetylation and transcriptional activation, TIP60 turned out to function as a haplo‐insufficient tumor suppressor in Eμ‐ myc mice . In this context, decreased TIP60 dosage did not cause transcriptional defects (whether considering MYC‐regulated or other loci), but instead impaired the buildup of an oncogene‐induced DDR in pretumoral Eμ‐ myc B‐cells, owing most likely to the direct action of TIP60 in DNA‐damage signaling: we surmise that TIP60, albeit suppressing tumor progression at early stages, remains a potential therapeutic target in established lymphomas. It is noteworthy here that, besides TIP60, the histone acetyltransferases p300/CREBBP and GCN5 are also transcriptional co‐factors of MYC, and that p300/CREBBP inhibitors suppressed MYC transcriptional activity and cell growth in the CML cell line K562 and in lymphoma cells with high MYC levels .…”

Orphan G Protein Coupled Receptors in Affective Disorders

“…However, no change in localization was observed when TIP60 was coexpressed with a truncated version of GPR50; while, co-transfection with the C-terminal tail of GPR50 induced a translocation of both TIP60 and the C-terminal tail to the nuclear compartment [ 170 ]. GPR50 enhances the TIP60 coactivation of GCR signaling, thereby revealing a potential role of GPR50 in the GC modulation of transcriptional programs [ 170 ] implicated in a number of physiological processes [ 173 ]. GPR50 and GPR61 mouse model studies have mainly focused on their role in metabolism [ 174 , 175 ]; however, the mRNA levels of brain derived neurotrophic factor (BDNF) in the hypothalamus were found lower in the GPR61 deficient mice compared to the wild-type littermates [ 174 ].…”