Trends in Cell Biology
Volume 16, Issue 9, September 2006, Pages 433-442
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Review
Tip60 in DNA damage response and growth control: many tricks in one HAT

https://doi.org/10.1016/j.tcb.2006.07.007Get rights and content

The Tip60 histone acetyltransferase is part of an evolutionarily conserved multisubunit complex, NuA4, which is recruited by many transcription factors to their target promoters, where it is thought to participate in histone acetylation and transcriptional activation. These transcription factors include tumor promoters and also tumor suppressors, such as p53, which links Tip60 to DNA damage responses. Tip60 also has transcription-independent roles in DNA damage responses. First, independently from NuA4, Tip60 binds the kinases ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and participates in their activation by DNA double-strand breaks. Second, NuA4 is recruited to the chromatin surrounding the breaks and, through a series of chromatin modifications, contributes to the dynamics of DNA repair. These molecular activities might endow Tip60 with multiple and potentially antagonistic biological functions.

Introduction

In eukaryotic cells, genomic DNA is packaged into chromatin. The basic unit of chromatin is the nucleosome, in which 145 base pairs of DNA are wrapped around a histone octamer comprising two copies of the core histones H2A, H2B, H3 and H4. Chromatin structure is highly dynamic and regulates virtually all DNA-associated processes, including transcription, replication and repair 1, 2. Chromatin is also the basis for epigenetic inheritance, by which the differential expression state of genes can be transmitted through successive cellular generations. There are two known broad classes of enzymes that modify chromatin and act in concert to regulate gene transcription 2, 3, 4. First, chromatin-remodeling enzymes use ATP hydrolysis to modify the histone composition or positioning of nucleosomes, without introducing covalent modifications in histones. Second, histone-modifying enzymes covalently modify chromatin by adding a variety of chemical moieties to specific histone residues. These enzymes are highly specific and belong to a variety of polypeptide families, which include histone acetyltransferases (HATs), deacetylases (HDACs), methyltransferases, demethylases, kinases, ubiquitin ligases and others.

Chromatin-modifying enzymes exist within large macromolecular complexes comprising multiple polypeptide subunits that modulate enzymatic activity, substrate specificity, chromatin association and site-specific recruitment by DNA-bound transcription factors (TFs). Tip60 is a HAT that is part of the evolutionarily conserved NuA4 complex [5], which acetylates nucleosomal histones H4 and H2A by the addition of an acetyl group to the ɛ-amino group of specific lysines. The NuA4 complex in metazoans incorporates two types of chromatin-modifying activities: a HAT (Tip60 itself) and an ATP-dependent chromatin remodeler (p400, also called Domino). This seems to correspond to two complexes in yeast (NuA4 and SWR1) which genetically and functionally overlap, and include orthologs of Tip60 and p400 (Esa1p and Swr1p) [5]. The subunit composition of NuA4 is highly conserved in Drosophila [6], and various subunits of a putative NuA4 complex have been identified in Caenorhabditis elegans as components of the same genetic complementation group [7]. The discovery, subunit composition and architecture of NuA4 have been discussed recently 5, 8, 9. The evidence linking Tip60 to transcriptional control has recently been reviewed [10] and is summarized in Box 1. Here, we discuss recent evidence linking Tip60 and NuA4 to key processes implicated in DNA damage response (DDR), DNA repair, cellular growth control and apoptosis. On this basis, we speculate that Tip60 might paradoxically function either as a promoter or as a suppressor of tumorigenesis.

Section snippets

Tip60 acts at multiple levels in DDR and DNA repair

The first indication that Tip60 might have a role in DDR and/or DNA repair came from transfection experiments in HeLa cells, in which overexpression of a dominant-negative allele of Tip60 reduced the efficiency of double-strand break (DSB) repair [11]. However, these experiments did not address whether Tip60 was required for damage sensing, signaling or repair. Recent work in different laboratories and experimental systems has implied that Tip60 might act at all those levels through several

The Tip60–NuA4 complex in growth control

The functions of Tip60 in DDR and transcriptional control are likely to contribute together and in a complex manner to the cellular responses to genotoxic stress. In particular, Tip60 has been directly linked to the transcriptional activity of p53, itself a downstream target of ATM–ATR signaling, a regulator of cell cycle arrest, senescence and apoptosis, as well as an important tumor suppressor. Here, we discuss recent findings that link Tip60 and other subunits of the NuA4 complex to these

Final considerations: role of Tip60 in tumorigenesis?

The findings summarized here highlight a complex and intricate network of interactions between Tip60 and pathways that regulate transcription, genomic stability, cell growth and apoptosis. The functional contributions and mechanisms of action of Tip60, p400 and other subunits of the NuA4 complex remain to be analyzed in detail. However, it is already clear that the biological activities of these proteins might be highly context dependent and are difficult to predict on a theoretical basis. For

Acknowledgements

We thank Gioacchino Natoli for critical reading of the manuscript, all members of our group for discussion and Pier-Giuseppe Pelicci for his support. Research in the Amati laboratory was supported by the Italian Association for Cancer Research (AIRC), by a ‘Ricerca Corrente’ grant from the Italian government and by the Association for International Cancer Research (UK).

References (101)

  • Z. Lou

    MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals

    Mol. Cell

    (2006)
  • X. Jiang

    The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM

    J. Biol. Chem.

    (2006)
  • J.A. Downs

    Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites

    Mol. Cell

    (2004)
  • R. Shroff

    Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break

    Curr. Biol.

    (2004)
  • A.J. Morrison

    INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair

    Cell

    (2004)
  • H. van Attikum

    Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair

    Cell

    (2004)
  • D. Chowdhury

    γ-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair

    Mol. Cell

    (2005)
  • G. Legube

    Role of the histone acetyl transferase Tip60 in the p53 pathway

    J. Biol. Chem.

    (2004)
  • S. Herold

    Negative regulation of the mammalian UV response by Myc through association with Miz-1

    Mol. Cell

    (2002)
  • N.E. Sharpless

    INK4a/ARF: a multifunctional tumor suppressor locus

    Mutat. Res.

    (2005)
  • F. Robert

    Global position and recruitment of HATs and HDACs in the yeast genome

    Mol. Cell

    (2004)
  • S. Gavaravarapu et al.

    Tip60 inhibits activation of CREB protein by protein kinase A

    Biochem. Biophys. Res. Commun.

    (2000)
  • H. Xiao

    Tip60 is a co-repressor for STAT3

    J. Biol. Chem.

    (2003)
  • L. Gaughan

    Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor

    J. Biol. Chem.

    (2002)
  • S.H. Baek

    Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-κB and β-amyloid precursor protein

    Cell

    (2002)
  • R. Metivier

    Estrogen receptor-α directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter

    Cell

    (2003)
  • A. Kinoshita

    The γ secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells

    J. Biol. Chem.

    (2002)
  • M.E. Brady

    Tip60 is a nuclear hormone receptor coactivator

    J. Biol. Chem.

    (1999)
  • L. Gaughan

    Tip60 is a co-activator specific for class I nuclear hormone receptors

    J. Biol. Chem.

    (2001)
  • C. Kramps

    E2F and Sp1/Sp3 synergize but are not sufficient to activate the MYCN gene in neuroblastomas

    J. Biol. Chem.

    (2004)
  • C. Kioussi

    Identification of a Wnt/Dvl/beta-Catenin  Pitx2 pathway mediating cell-type-specific proliferation during development

    Cell

    (2002)
  • M.S. Kim

    Co-activation of atrial natriuretic factor promoter by Tip60 and serum response factor

    J. Biol. Chem.

    (2006)
  • M.R. Barron

    Serum response factor, an enriched cardiac mesoderm obligatory factor, is a downstream gene target for Tbx genes

    J. Biol. Chem.

    (2005)
  • H.J. Lee

    Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signalling

    J. Biol. Chem.

    (2001)
  • D. Sliva

    Tip60 interacts with human interleukin-9 receptor alpha-chain

    Biochem. Biophys. Res. Commun.

    (1999)
  • I.R. Logan

    Control of human PIRH2 protein stability: involvement of TIP60 and the proteosome

    J. Biol. Chem.

    (2004)
  • H. Zhang

    Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss

    Cell

    (2005)
  • R.M. Raisner

    Histone variant H2A.Z marks the 5′ ends of both active and inactive genes in euchromatin

    Cell

    (2005)
  • M. Fuchs

    The p400 complex is an essential E1A transformation target

    Cell

    (2001)
  • A.V. Samuelson

    p400 is required for E1A to promote apoptosis

    J. Biol. Chem.

    (2005)
  • J. Kamine

    Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator

    Virology

    (1996)
  • C.L. Peterson et al.

    Cellular machineries for chromosomal DNA repair

    Genes Dev.

    (2004)
  • D.E. Sterner et al.

    Acetylation of histones and transcription-related factors

    Microbiol. Mol. Biol. Rev.

    (2000)
  • T. Kusch

    Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions

    Science

    (2004)
  • A. Sancar

    Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

    Annu. Rev. Biochem.

    (2004)
  • J.H. Lee et al.

    ATM activation by DNA double-strand breaks through the Mre11–Rad50–Nbs1 complex

    Science

    (2005)
  • E.P. Rogakou

    Megabase chromatin domains involved in DNA double-strand breaks in vivo

    J. Cell Biol.

    (1999)
  • Y. Sun

    A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • A.A. Boudreault

    Yeast enhancer of polycomb defines global Esa1-dependent acetylation of chromatin

    Genes Dev.

    (2003)
  • R. Murr

    Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks

    Nat. Cell Biol.

    (2006)
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