Mechanistic Links Between ATM and Histone Methylation Codes During DNA Repair - Progress in Molecular Biology - page 258

Mechanistic Links Between
ATM and Histone Methylation
Codes During DNA Repair

Ye Xu, Chang Xu, and
Brendan D. Price
Division of Genome Stability and DNA
Repair, Department of Radiation Oncology,
Dana-Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts,
USA

I. The DNA Damage Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

II. Ataxia telangiectasia and the ATM Kinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

A. Cellular Defects in ataxia telangiectasia .......................................... 266

B. Activation of the ATM Kinase by DSBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

C. ATM and the mre11-rad50-nbs1 Complex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

D. Other Contributors to ATM Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

III. The Tip60 Acetyltransferase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

A. Tip60 Is a Ubiquitously Expressed Acetyltransferase . . . . . . . . . . . . . . . . . . . . . . . . . 269

B. Tip60 and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

C. Tip60 and ATM Acetylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270

D. Activation of Tip60 by DSBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

E. Interaction Between ATM Tip60 and the MRN Complex . . . . . . . . . . . . . . . . . . . 273

IV. H3K9me3 and DDR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

A. Tip60 Activation by Preexisting H3K9me3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

B. Tip60 Activation by Inducible H3K9 Methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

C. A Special Role for Heterochromatin in ATM Function? . . . . . . . . . . . . . . . . . . . . . 277

D. Chromatin Dynamics and ATM Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

V. Conclusions and Implications for Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

The ataxia telangiectasia-mutated (ATM) protein kinase is the master regu-
lator of the DNA double-strand break (DSB) repair pathway. The activation of
ATM involves its recruitment to the DSB through interaction with the
mre11-rad50-nbs1 complex, followed by the acetylation of ATM by the
Tip60 acetyltransferase. This acetylation of ATM within its regulatory domain
is essential for activating ATM's kinase activity. Further work has now revealed
that Tip60 is activated through direct interaction between Tip60's chromodo-
main and histone H3 trimethylated on lysine 9 (H3K9me3). The loading of
Tip60 onto the chromatin at DSBs therefore represents the primary mecha-
nism for activation of Tip60's acetyltransferase activity in response to DNA
damage. The ability of H3K9me3 at DSBs to regulate the activity of Tip60 and
the subsequent activation of ATM emphasizes the crucial role played by
chromatin architecture in regulating DSB repair. Further, histone methylation