Review
Cellular functions of TIP60

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Abstract

TIP60 was originally identified as a cellular acetyltransferase protein that interacts with HIV-1 Tat. As a consequence, the role of TIP60 in transcriptional regulation has been investigated intensively. Recent data suggest that TIP60 has more divergent functions than originally thought and roles for TIP60 in many processes, such as cellular signalling, DNA damage repair, cell cycle and checkpoint control and apoptosis are emerging. TIP60 is a tightly regulated transcriptional coregulator, acting in a large multiprotein complex for a range of transcription factors including androgen receptor, Myc, STAT3, NF-κB, E2F1 and p53. This usually involves recruitment of TIP60 acetyltransferase activities to chromatin. Additionally, in response to DNA double strand breaks, TIP60 is recruited to DNA lesions where it participates both in the initial as well as the final stages of repair. Here, we describe how TIP60 is a multifunctional enzyme involved in multiple nuclear transactions.

Introduction

Acetyltransferases are enzymes that catalyse the transfer of acetyl groups from acetyl coenzyme A to either the α-amino group of N-terminal amino acids or the ɛ-amino group of internal lysine residues. N-terminal acetylation occurs during translation in the majority of eukaryotic proteins. Lysine acetylation is a post-translational modification that affects many protein functions, including DNA binding, protein–protein interactions, enzymatic activity and stability (Polevoda & Sherman, 2002). A multitude of proteins are modified by lysine acetylation, including histones, high mobility group (HMG) proteins, transcription factors and nuclear import factors (Polevoda & Sherman, 2002). The best characterised examples of lysine-acetylated proteins are histones. Histone acetylation regulates chromatin accessibility and in combination with other post-translational modifications, creates a multisite modification code (histone code), which is recognised by transcriptional proteins in order to regulate transcription (Strahl & Allis, 2000; Turner, 2002).

Lysine acetyltransferases fall into several categories, one of which is the MYST family, named after its founding members: MOZ, Ybf2/Sas3, Sas2 and TIP60. MYST family members function in a broad range of biological processes, such as gene regulation, dosage compensation, DNA damage repair and tumourigenesis (Utley & Cote, 2003). Although MYST proteins seem to have diverse cellular roles, all family members are characterised by the highly conserved MYST acetyltransferase domain and most MYST enzymes exist as the catalytic subunits of multiprotein complexes.

TIP60, one of the best characterised MYST proteins, is a human homologue with relevance to human pathology. This review will summarise what is known about Tat-interactive protein 60 kDa (TIP60), focusing on its involvement in transcription and DNA damage response.

Section snippets

HTATIP gene

TIP60 was originally isolated as a HIV-1 Tat interactive protein (Kamine, Elangovan, Subramanian, Coleman, & Chinnadurai, 1996). The HTATIP gene encoding TIP60 is located at 11q13.1 and consists of 14 exons. Alternative splicing results in the expression of at least three splice variants, TIP60 isoform 1, TIP60 isoform 2 (TIP60α) and TIP60 isoform 3 (TIP60β, PLA2 interacting protein, PLIP). The best characterised splice variant is isoform 2. Isoform 1 arises from translation of intron 1 and

Acetyltransferase activity

Shortly after its discovery it became evident that TIP60 possesses histone acetyltransferase (HAT) activity. Recombinant TIP60 acetylates core histones H2A (Lys5), H3 (Lys14) and H4 (Lys5, Lys8, Lys12 and Lys16 in vitro; Kimura & Horikoshi, 1998; Yamamoto & Horikoshi, 1997). When in a stable multiprotein complex, TIP60 can also modify in vitro histones assembled into nucleosomes; in this case, TIP60 selectively targets nucleosomal H2A and H4 (Ikura et al., 2000). Recent evidence from D.

TIP60 complex

Depending on the cellular process in which it participates, TIP60 forms distinct transient complexes with the appropriate binding partners. However, the majority of cellular TIP60 exists in a stable nuclear multiprotein complex (Table 1) that consists of at least 18 subunits and performs most transcriptional and DNA damage-related TIP60 functions.

Central to the TIP60 stable complex is the scaffold protein transformation/transcription domain-associated protein (TRRAP) (Ikura et al., 2000), which

Cytoplasmic TIP60

Both TIP60α and TIP60β are predominantly nuclear proteins involved in nuclear processes (Cao & Sudhof, 2001; Gavaravarapu & Kamine, 2000; Ran & Pereira-Smith, 2000; Sheridan et al., 2001, Yamamoto and Horikoshi, 1997). However, in some cases TIP60 has been found to localise in the cytoplasm in association with internalised membrane receptors thus regulating downstream kinase pathways or gene expression. For example, TIP60 is involved in interleukin-9 (IL-9) signalling, a cytokine promoting

Nuclear receptor coactivation and involvement in prostate cancer

Soon after its discovery, TIP60 was found to be involved in nuclear receptor (NR) signalling and to be a NR-coregulator. TIP60 binds to the ligand binding domain of AR and other NRs via a single NR-box that comprises the Leu-X-X-Leu-Leu motif near the TIP60 C-terminus and thus coregulates NR mediated gene expression (Brady et al., 1999, Gaughan et al., 2001). TIP60 predominantly coactivates NR transactivation of genes, although there have been reports of TIP60-dependent NR corepression (Sharma,

Regulation of TIP60 protein

Based on the data presented above, it is apparent that TIP60 is an important cofactor of several nuclear as well as cytoplasmic processes. This implies that TIP60 expression, stability, activity and localisation should be tightly regulated in the cell by various modes.

So far, regulation of TIP60 by protein binding and post-translational modifications has been documented. Complex formation modifies TIP60 function and acetyltransferase activity and only in the context of the nuclear complex

Involvement of TIP60 in the p53 pathway

Indications that TIP60 is involved in the p53 pathway initially arose from the fact that TIP60 and p53 share some functional similarities: both proteins are regulated by the human homologue of Mdm2 which catalyses their ubiquitylation and proteosomal degradation, levels of both proteins accumulate after DNA damage and both share binding partners, such as PIRH2 (Legube et al., 2002, Logan et al., 2004). The TIP60 complex also contains the tumour suppressor ING3, a component of the p53 pathway (

Role of TIP60 in apoptosis

TIP60 is believed to be involved in the initiation of apoptotic pathways. The acetyltransferase activity of TIP60 is essential for sensing DNA damage and triggering apoptosis while cells expressing HAT-deficient TIP60 exhibit severe defects in apoptosis after γ-irradiation (Ikura et al., 2000). The exact mechanism of this effect is unclear, but is possibly dependent on p53. Components of the TIP60 complex, such as the proapoptotic protein ING3 are considered in part responsible for the

TIP60 and DNA double strand break response

Eukaryotic genomes are packaged in chromatin; therefore an efficient DNA damage response requires changes in chromatin architecture. Accumulating data confirm that acetyltransferases play an important role in DNA damage response.

Cells expressing catalytically inactive TIP60 accumulate double strand DNA breaks, indicating that TIP60 is crucial for damage repair (Ikura et al., 2000). The TIP60 complex is capable of binding structural DNA intermediates involved in DNA repair and replication. This

TIP60 involvement in the mitotic checkpoint

Downregulation of TIP60 leads to deregulation of cell cycle checkpoints after ionising radiation (Berns et al., 2004). Moreover, TIP60 is involved in the maintenance of genomic stability by participating in the regulation of the mitotic checkpoint. The mitotic checkpoint prevents onset of anaphase in cases of incorrect chromosome segregation during cell division by blocking anaphase promoting complex (APC). Mitotic arrest deficient 1/2 (Mad1 and Mad2) proteins are key components of the mitotic

Concluding remarks

TIP60 is a protein with multiple roles, affecting the functions of a diverse variety of targets, including transcriptional regulators, cell cycle and checkpoint machinery and DNA repair regulators. It does so using its acetyltransferase activity but also by directed protein–protein interactions and sequestration of binding partners to specific compartments.

Future research should focus on understanding how this multifaceted protein is regulated to gain insight into the exact mechanism of

Acknowledgements

VS is funded by Harker Foundation Newcastle University and IRL is funded by European Union Framework 6 (PRIMA programme grant). Thanks to Arthur Mckie for critical proofreading.

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