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

Murr, Rabih; Loizou, Joanna I.; Yang, Yun‐Gui; Cuenin, Cyrille; Li, Hai; Wang, Zhaoqi; Herceg, Zdenko

doi:10.1038/ncb1343

Cited by 552 publications

(592 citation statements)

References 35 publications

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“…Our present studies validated that Lys 430 and Lys 451 are indeed the substrates for SUMO1 and essential for DNA damage response. It has been shown that TIP60 regulates the ATM/ATR activation caused by ionizing radiation (Sun et al, 2005) and participates in UV-induced DNA damage repair (Murr et al, 2006). Identification of TIP60 sumoylation provides great insight into the molecular mechanisms underlying DNA damage responses to UV irradiation vs ionizing radiation.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

Cheng

Ke²,

Ding

et al. 2007

Oncogene

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“…In particular, the N-terminal lysine residues of histones H3 and H4 are acetylated during DSBs (Bird et al, 2002;Tamburini and Tyler, 2005). Consistent with this, NuA4-Tip60 HAT acetylates histone H4 at DSB sites and facilitates DSB repair (Bird et al, 2002;Murr et al, 2006). In addition to HATs, the SWI2/SNF2 superfamily (INO80, SWR1, SWI/SNF and RSC) chromatin remodeling complexes are recruited to DSB sites and facilitate alterations in the nucleosomal position.…”

Section: Introductionmentioning

confidence: 68%

“…Acetylation of the N-terminal lysines 5, 8, 12 and 16 within histone H4 (H4 K5/K8/K12/K16) is critical for NHEJ (Bird et al, 2002). TIP60 functions as an acetyltransferase for the N-terminal residues of histone H4 at DSB sites in both yeast and mammalian cells (Downs et al, 2004; Role of CBP/p300 in non-homologous end joining H Ogiwara et al Murr et al, 2006). However, it was not known whether TIP60 is required for NHEJ in vivo.…”

Section: Discussionmentioning

confidence: 99%

Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors

Ogiwara¹,

et al. 2011

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Non-homologous end joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs) generated by ionizing radiation (IR) and anti-cancer drugs. Therefore, inhibiting the activity of proteins involved in this pathway is a promising way of sensitizing cancer cells to both radiotherapy and chemotherapy. In this study, we developed an assay for evaluating NHEJ activity against DSBs in chromosomal DNA in human cells to identify the chromatin modification/remodeling proteins involved in NHEJ. We showed that ablating the activity of the homologous histone acetyltransferases, CBP and p300, using inhibitors or small interfering RNAs-suppressed NHEJ. Ablation of CBP or p300 impaired IR-induced DSB repair and sensitized lung cancer cells to IR and the anti-cancer drug, etoposide, which induces DSBs that are repaired by NHEJ. The CBP/p300 proteins were recruited to sites of DSBs and their ablation suppressed acetylation of lysine 18 within histone H3, and lysines 5, 8, 12, and 16 within histone H4, at the DSB sites. This then suppressed the recruitment of KU70 and KU80, both key proteins for NHEJ, to the DSB sites. Ablation of CBP/p300 also impaired the recruitment of BRM, a catalytic subunit of the SWI/SNF complex involved in chromatin remodeling at DSB sites. These results indicate that CBP and p300 function as histone H3 and H4 acetyltransferases at DSB sites in NHEJ and facilitate chromatin relaxation. Therefore, inhibition CBP and p300 activity may sensitize cancer cells to radiotherapy and chemotherapy.

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“…The p400/Tip60 ratio and cell proliferation L Mattera et al (Murr et al, 2006), this finding could merely be an indirect consequence of the activation of DDR pathways by p400 knockdown. Strikingly, Tip60 directly acetylates the DNA damage signaling protein ATM (Sun et al, 2005), therefore allowing its activation.…”

Section: Discussionmentioning

confidence: 96%

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

Cited by 552 publications

References 35 publications

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

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

Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors

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

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