Role of the Histone Acetyl Transferase Tip60 in the p53 Pathway

Legube, Gaëlle; Linares, Laëtitia K.; Tyteca, Sandrine; Caron, Cécile; Scheffner, Martin; Chevillard-Briet, Martine; Trouche, Didier

doi:10.1074/jbc.m407478200

Cited by 125 publications

(155 citation statements)

References 33 publications

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“…To assess the function of TIP60 in UV-induced DNA damage response, we introduced siRNA oligonucleotides to suppress TIP60 protein level. As reported previously (for example, Legube et al, 2004), the siRNA duplexes suppress TIP60 protein accumulation ( Figure 4A). …”

Section: Uv Irradiation Induces the Sumoylation Of Tip60 At Lysines 4supporting

confidence: 89%

“…ATR/Chk2 phosphorylates p53 at Ser 20 and stabilize p53 protein levels (for example, Legube et al, 2004). Sun et al (2005) demonstrated that TIP60 HAT activates ATM autophosphorylation in response to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…Cells expressing mutated TIP60 lacking acetylase activity failed to undergo apoptosis in response to DNA damage (for example, Ikura et al, 2000). Like p53, TIP60 accumulates in response to DNA damage (for example, Legube et al, 2004). Suppression of TIP60 blocks ATM activation and ATM-dependent phosphorylation of p53, suggesting that TIP60 is an upstream molecule in ATMdependent DNA damage response (Sun et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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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: Uv Irradiation Induces the Sumoylation Of Tip60 At Lysines 4supporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cheng

Ke²,

Ding

et al. 2007

Oncogene

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“…In agreement with its function in histone acetylation, Tip60 is mainly involved in transcriptional activation of specific genes (Gaughan et al, 2001;Berns et al, 2004;Legube et al, 2004). Transcriptional regulation of some genes, such as E2F or c-mycdependent genes, most likely involves the whole Tip60 complex (Frank et al, 2003;Taubert et al, 2004).…”

Section: Introductionmentioning

confidence: 87%

“…As in many other cancer cells, TSA treatment strongly induces apoptosis ( Figure 3a). Importantly, this apoptosis is inhibited by siRNA directed against Tip60 (described in Legube et al (2004) and Tyteca et al (2006)), indicating that Tip60 expression is, at least in part, required for TSA-induced apoptosis (the efficiency of the knockdown was checked by western blot and RT-QPCR ( Figure 3b). This result thus shows that the Tip60-dependent apoptotic pathways are functional in these cells and that activating endogenous Tip60 function is sufficient to promote apoptosis.…”

Section: Tip60 Function Is Rate Limiting For Apoptosis In Hct116 Cellsmentioning

confidence: 99%

The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

et al. 2009

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The Tip60 histone acetyltransferase belongs to a multimolecular complex that contains many chromatin remodeling enzymes including the ATPase p400, a protein involved in nucleosomal incorporation of specific histone variants and that can directly or indirectly repress some Tip60-dependent pathways. Tip60 activity is critical for the cellular response to DNA damage and is affected during cancer progression. Here, we found that the ratio between Tip60 and p400 mRNAs is affected in most colorectal carcinoma. Strikingly, reversing the p400/ Tip60 imbalance by Tip60 overexpression or the use of siRNAs resulted in increased apoptosis and decreased proliferation of colon-cancer-derived cells, suggesting that this ratio defect is important for cancer progression. Furthermore, we demonstrate that the p400/Tip60 ratio controls the oncogene-induced DNA damage response, a known anticancer barrier. Finally, we found that it is also critical for the response to 5-fluorouracil, a first-line treatment against colon cancer. Together, our data indicate that the p400/Tip60 ratio is critical for colon cancer cells proliferation and response to therapeutic drugs through the control of stress-response pathways.

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Regulation of Tip60‐dependent p53 acetylation in cell fate decision

et al. 2018

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The acetylation of p53 plays an essential role in regulating its transcriptional activity. Nevertheless, how p53 acetylation is modulated in cell fate decision is less understood. We developed a network model to reveal how Tip60‐dependent p53 acetylation is regulated to modulate cellular outcome. We proposed that p53 is progressively activated and exhibits distinct dynamics depending on the severity of DNA damage. For mild damage, p53 is primarily activated to trigger cell cycle arrest by transactivating p21, with its concentration showing pulses. For severe damage, p53 is acetylated at Lysine 120 (K120) by Tip60 to trigger apoptosis by inducing PUMA, and its concentration increases to high levels. Several p53‐centered feedback loops coordinate to regulate its acetylation status, ensuring a robust decision on cell fate.

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Role of the Histone Acetyl Transferase Tip60 in the p53 Pathway

Cited by 125 publications

References 33 publications

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

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

The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

Regulation of Tip60‐dependent p53 acetylation in cell fate decision

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