title: Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair.
abstract: The repair of DNA double-strand breaks (DSBs) requires open, flexible chromatin domains. The NuA4-Tip60 complex creates these flexible chromatin structures by exchanging histone H2A.Z onto nucleosomes and promoting acetylation of histone H4. Here, we demonstrate that the accumulation of H2A.Z on nucleosomes at DSBs is transient, and that rapid eviction of H2A.Z is required for DSB repair. Anp32e, an H2A.Z chaperone that interacts with the C-terminal docking domain of H2A.Z, is rapidly recruited to DSBs. Anp32e functions to remove H2A.Z from nucleosomes, so that H2A.Z levels return to basal within 10 min of DNA damage. Further, H2A.Z removal by Anp32e disrupts inhibitory interactions between the histone H4 tail and the nucleosome surface, facilitating increased acetylation of histone H4 following DNA damage. When H2A.Z removal by Anp32e is blocked, nucleosomes at DSBs retain elevated levels of H2A.Z, and assume a more stable, hypoacetylated conformation. Further, loss of Anp32e leads to increased CtIP-dependent end resection, accumulation of single-stranded DNA, and an increase in repair by the alternative nonhomologous end joining pathway. Exchange of H2A.Z onto the chromatin and subsequent rapid removal by Anp32e are therefore critical for creating open, acetylated nucleosome structures and for controlling end resection by CtIP. Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA 02215.
authors.forename: Ozge
authors.initials: O
authors.lastname: Gursoy-Yuzugullu
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA 02215.
authors.forename: Marina K
authors.initials: MK
authors.lastname: Ayrapetov
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA 02215 brendan_price@dfci.harvard.edu.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Price
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D057809:HEK293 Cells; D006367:HeLa Cells; D056488:Histone Chaperones / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs
chemical_list: C490336:ANP32E protein, human; D002352:Carrier Proteins; D056488:Histone Chaperones; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D009707:Nucleosomes; D010750:Phosphoproteins; C077020:histone H2A.F-Z; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human
keywords: Anp32e; DSB repair; H2A.Z; NHEJ; genome instability