Trends in Cell Biology
ReviewTip60 in DNA damage response and growth control: many tricks in one HAT
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).
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