Tip60: connecting chromatin to DNA damage signaling - PubMed (original) (raw)

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Tip60: connecting chromatin to DNA damage signaling

Yingli Sun et al. Cell Cycle. 2010.

Abstract

Cells are constantly exposed to genotoxic events that can damage DNA. To counter this, cells have evolved a series of highly conserved DNA repair pathways to maintain genomic integrity. The ATM protein kinase is a master regulator of the DNA double-strand break (DSB) repair pathway. DSBs activate ATM's kinase activity, promoting the phosphorylation of proteins involved in both checkpoint activation and DNA repair. Recent work has revealed that two DNA damage response proteins, the Tip60 acetyltransferase and the mre11- rad50-nbs1 (MRN) complex, co-operate in the activation of ATM in response to DSBs. MRN functions to target ATM and the Tip60 acetyltransferase to DSBs. Tip60's chromodomain then interacts with histone H3 trimethylated on lysine 9, activating Tip60's acetyltransferase activity and stimulating the subsequent acetylation and activation of ATM's kinase activity. These results underscore the importance of chromatin structure in regulating DNA damage signaling and emphasize how histone modifications co-ordinate DNA repair. In addition, human tumors frequently exhibit altered patterns of histone methylation. This rewriting of the histone methylation code in tumor cells may impact the efficiency of DSB repair, increasing genomic instability and contributing to the initiation and progression of cancer.

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Figures

Figure 1

Figure 1. Acetylation and activation of ATM by Tip60

Domain structure of ATM, including the PIK Regulatory Domain (PRD) and the conserved FAT and FATC domains. ? Indicates unidentified protein factor(s) hypothesized to be required for recruiting Tip60 to the ATM complex. IR = Ionizing Radiation, Ac = acetylation.

Figure 2

Figure 2. A mechanism for ATM activation

STEP 1: Following DSB production, MRN is recruited to DSB. In parallel, HP1 proteins are released from H3K9me3, and either retained on the chromatin, or released to the nucleoplasm by a process involving phosphorylation of HP1 by the CK2 kinase . It is not know if MRN participates in this process. STEP 2: Inactive ATM-Tip60 complex is recruited to the DSB by MRN, facilitating interactions between Tip60's chromodomain and H3K9me3. STEP 3: Interaction between MRN and ATM, in combination with acetylation of ATM by Tip60, activates ATM's kinase activity. Me = methylation, Ac = acetylation, P = phosphorylation.

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