title: Tip60: connecting chromatin to DNA damage signaling.
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.
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jiang
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Price
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism* / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D000076228:MRE11 Homologue Protein; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C121766:MRE11 protein, human; D025521:Tumor Suppressor Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein