Acetylation by Tip60 Is Required for Selective Histone Variant Exchange at DNA Lesions

Kusch, T; Florens, Laurence; MacDonald, WA; Swanson, Selene K.; Glaser, Robert L.; Yates, John R.; Abmayr, Susan M.; Washburn, Michael P.; Workman, Jerry L.

doi:10.1126/science.1103455

Cited by 617 publications

(658 citation statements)

References 26 publications

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“…SUMO modifying enzymes form a complex with TIP60 in response to UV irradiation TIP60 plays an important role in the DNA damage repair (for example, Kusch et al, 2004), and the UV irradiation induces TIP60 translocation into punctuate subnuclear structures named nuclear bodies (NBs; also called promyelocyti leukemia (PML) bodies) in 293T cells (for example, Supplementary Figure S1). To further understand the role of TIP60 in the UV irradiationmediated DNA damage response and identify the proteins that account for the UV-induced translocation of TIP60, we carried out a proteomic search for nuclear proteins that bind to TIP60 in response to UV irradiation.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response

Cheng

Ke²,

Ding

et al. 2007

Oncogene

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The histone acetyltransferase TIP60 regulates the DNA damage response following genotoxic stress by acetylating histone and remodeling chromatin. However, the molecular mechanisms underlying the TIP60-dependent response to UV-induced DNA damage remain poorly understood. To systematically analyse proteins that regulate TIP60 activity in response to UV irradiation, we performed a proteomic analysis of proteins selectively bound to TIP60 in response to UV irradiation using mass spectrometry and identified a novel regulatory mechanism by which TIP60 orchestrates transcriptional activation of p53-dependent checkpoint response in UV-irradiated cells. The initial step of this pathway involves UV-induced association of TIP60 with SUMO-conjugation enzymes and site-specific sumoylation of TIP60 at lysines 430 and 451 via Ubc9. This sumoylation initiates the relocation of TIP60 from nucleoplasm to the promyelocytic leukemia body, which is essential for the UV-irradiated DNA damage repair response via a p53-dependent pathway. Significantly, inhibition of TIP60 sumoylation by overexpression of non-sumoylatable mutant abrogates the p53-dependent DNA damage response, demonstrating the importance of TIP60 sumoylation in response to UV irradiation. Our biochemical characterization demonstrated that the sumoylation of TIP60 augments its acetyltransferase activity in vitro and in vivo. Thus, this study shed new light on the function and regulation of TIP60 activity in UV-irradiated DNA damage response.

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Section: Resultsmentioning

confidence: 99%

Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response

Cheng

Ke²,

Ding

et al. 2007

Oncogene

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“…It is now known that MYST proteins have important roles in various biological processes (Ceol and Horvitz, 2004;Kusch et al, 2004;Dou et al, 2005;Smith et al, 2005;Mendjan et al, 2006;Sykes et al, 2006;Tang et al, 2006). These enzymes have been the subjects of several excellent reviews Squatrito et al, 2006;Avvakumov and Coˆte´, 2007;Lafon et al, 2007;Rea et al, 2007;Thomas and Voss, 2007).…”

Section: Identification Of Moz Morf and Other Mystic Hatsmentioning

confidence: 99%

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

2007

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Genes of the human monocytic leukemia zinc-finger protein MOZ (HUGO symbol, MYST3) and its paralog MORF (MYST4) are rearranged in chromosome translocations associated with acute myeloid leukemia and/or benign uterine leiomyomata. Both proteins have intrinsic histone acetyltransferase activity and are components of quartet complexes with noncatalytic subunits containing the bromodomain, plant homeodomain-linked (PHD) finger and proline-tryptophan-tryptophan-proline (PWWP)-containing domain, three types of structural modules characteristic of chromatin regulators. Although leukemia-derived fusion proteins such as MOZ-TIF2 promote self-renewal of leukemic stem cells, recent studies indicate that murine MOZ and MORF are important for proper development of hematopoietic and neurogenic progenitors, respectively, thereby highlighting the importance of epigenetic integrity in safeguarding stem cell identity.

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“…2B). The exchange of phosphorylated Drosophila H2Av around DSBs for unphosphorylated H2Av requires the Tip60 protein complex, which has both histone acetyl transferase and ATP-dependent chromatin remodeling activities [99]. Tip60 has also been linked to many earlier stages in DNA damage signaling and double-strand DNA repair, although this is mainly through its histone acetyl transferase activity (see Chapter X).…”

Section: The Consequences Of Failure To Assemble and Disassemble Chromentioning

confidence: 99%

Chromatin disassembly and reassembly during DNA repair

Linger

Tyler

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Current research is demonstrating that the packaging of the eukaryotic genome together with histone proteins into chromatin is playing a fundamental role in DNA repair and the maintenance of genomic integrity. As is well established to be the case for transcription, the chromatin structure dynamically changes during DNA repair. Recent studies indicate that the complete removal of histones from DNA and their subsequent reassembly onto DNA accompanies DNA repair. This review will present evidence indicating that chromatin disassembly and reassembly occur during DNA repair and that these are critical processes for cell survival after DNA repair. Concomitantly, candidate proteins utilized for these processes will be highlighted.

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Acetylation by Tip60 Is Required for Selective Histone Variant Exchange at DNA Lesions

Cited by 617 publications

References 26 publications

Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response

Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

Chromatin disassembly and reassembly during DNA repair

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