Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60
Open accessAbstract
DNA double-strand break (DSB) repair involves complex interactions between chromatin and repair proteins, including Tip60, a tumour suppressor. Tip60 is an acetyltransferase that acetylates both histones and ATM (ataxia telangiectasia mutated) kinase. Inactivation of Tip60 leads to defective DNA repair and increased cancer risk. However, how DNA damage activates the acetyltransferase activity of Tip60 is not known. Here, we show that direct interaction between the chromodomain of Tip60 and histone H3 trimethylated on lysine 9 (H3K9me3) at DSBs activates the acetyltransferase activity of Tip60. Depletion of intracellular H3K9me3 blocks activation of the acetyltransferase activity of Tip60, resulting in defective ATM activation and widespread defects in DSB repair. In addition, the ability of Tip60 to access H3K9me3 is dependent on the DNA damage-induced displacement of HP1beta (heterochromatin protein 1beta) from H3K9me3. Finally, we demonstrate that the Mre11-Rad50-Nbs1 (MRN) complex targets Tip60 to H3K9me3, and is required to activate the acetyltransferase activity of Tip60. These results reveal a new function for H3K9me3 in coordinating activation of Tip60-dependent DNA repair pathways, and imply that aberrant patterns of histone methylation may contribute to cancer by altering the efficiency of DSB repair.
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Loss of MRN, Tip60, or acute PARP inhibition leads to defective activation of ATM's kinase activity.
“This finding is consistent with published studies in which loss of MRN (2), Tip60 (4, 6), or acute PARP inhibition (35) led to defective activation of ATM's kinase activity.”
From DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin (2014) · cites this paper as [4]
The introductory paragraph reports that mutations disabling Tip60’s chromodomain blocked ATM acetylation and autophosphorylation, with a profound defect in ATM activation (Fig. 1b and Fig. S2b). This supports defective ATM activation when Tip60 function is impaired, but the paper tests functional mutations rather than loss of Tip60 itself. The MRN and PARP clauses are attributed to other citations in the citing sentence. (LLM, conf=0.83)
Experimental — accuracy not yet measuredLoss of H3K9me2/3 leads to failure to activate the ATM signaling pathway, loss of H4 acetylation during DSB repair, disruption of heterochromatin, genomic instability, and defective DSB repair.
“Consequently, loss of H3K9me2/3 leads to failure to activate the ATM signaling pathway, loss of H4 acetylation during DSB repair, disruption of heterochromatin, genomic instability, and defective DSB repair (4,(17)(18)(19).”
From DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin (2014) · cites this paper as [4]
The introductory paragraph and the discussion of Figure 4 report that reducing H3K9me3 impairs Tip60-dependent ATM activation and DSB repair. The paper also reports increased genomic instability in Suv39h1/2-deficient mice, but does not establish the claimed loss of H4 acetylation or address H3K9me2 in this pathway. It does not show that demethylation disrupts heterochromatin; the Figure 4 discussion says it did not impose structural chromatin changes that inhibited damage signaling. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredH3K9me3 is required for activation of the Tip60 acetyltransferase.
“H3K9me3 is required for activation of the Tip60 acetyltransferase (4, 17).”
From DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin (2014) · cites this paper as [4]
PARPi inhibits phosphorylation of kap-1 by ATM after DNA damage.
“In addition, because H3K9me3 is important for full activation of ATM (4), PARPi also inhibited phosphorylation of kap-1 by ATM after DNA damage (Fig. 6B).”
From DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin (2014) · cites this paper as [4]
Activation of Tip60's acetyltransferase activity requires interaction between Tip60's chromodomain and H3K9me3 on nucleosomes at the break.
“Activation of Tip60's acetyltransferase activity requires interaction between Tip60's chromodomain and histone H3 methylated on lysine 9 (H3K9me3) on nucleosomes at the break (4,6).”
From DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin (2014) · cites this paper as [4]
H3K9me3 stimulates binding and activation of TIP60 after DNA damage, which acetylates ATM and promotes its activation.
“H3K9me3 is known to stimulate binding and activation of the TIP60 acetyltransferase after DNA damage”
From Activation of DNA Damage Response Signaling by Condensed Chromatin (2014) · cites this paper as Sun et al., 2009
The H3K9me3 repressive mark creates binding sites for TIP60 acetyltransferase, which contributes to amplifying ATM activity.
“Formation of a H3K9me3 repressive mark creates binding sites for the TIP60 acetyltransferase, which then contributes to the amplification of ATM activity (Ayrapetov et al., 2014; Sun et al., 2005; Sun et al., 2009).”
From Activation of DNA Damage Response Signaling by Condensed Chromatin (2014) · cites this paper as Sun et al., 2009
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- Authors
- Sun, Y., Jiang, X., Xu, Y., Ayrapetov, M. K., Moreau, L. A., Whetstine, J. R., & Price, B. D.
- Affiliations
- Harvard University (US)
- Corresponding author
- Price, Brendan D.
- Venue
- Nature Cell Biology
- Published
- 2009-09-27
- Volume
- 11
- Issue
- 11
- Pages
- 1376-1382
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2783526
- OpenAlex
- W174577041
- Cited by
- 454
- References
- 38
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 22 · 2023: 20 · 2022: 30 · 2021: 18 · 2020: 24 · 2019: 25 · 2018: 38 · 2017: 38 · 2016: 30 · 2015: 31 · 2014: 33 · 2013: 32 · 2012: 34
- FWCI
- 11.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (T32 CA09078, R01CA064585, R01CA093602, CA64585, T32CA009078, CA93602)
- National Institute of Allergy and Infectious Diseases (U19AI067751)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Tip60, histone H3 lysine 9 trimethylation, H3K9me3, DNA double-strand break repair, ATM kinase activation, histone acetylation, chromodomain, Mre11-Rad50-Nbs1 complex, tumour suppressor, DNA damage response, heterochromatin
- MeSH terms
- Lysine Acetyltransferase 5, Chromobox Protein Homolog 5, DNA Damage, HeLa Cells, Histones, Humans, Genes, Tumor Suppressor, DNA Methylation, Histone Acetyltransferases
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