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PMID:19282473

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Citation

Stante, M, Minopoli, G, Passaro, F, Raia, M, Vecchio, LD and Russo, T (2009) Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks. Proc. Natl. Acad. Sci. U.S.A. 106:5093-8

Abstract

Fe65 is a binding partner of the Alzheimer's beta-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites.

Links

PubMed PMC2664056 Online version:10.1073/pnas.0810869106

Keywords

Acetylation; Adaptor Proteins, Signal Transducing/metabolism; Amyloid beta-Protein Precursor/metabolism; Animals; DNA Breaks; DNA Repair; Histone Acetyltransferases/metabolism; Histones/metabolism; Mice; Nerve Tissue Proteins/physiology; Nuclear Proteins/metabolism; Nuclear Proteins/physiology; Protease Nexins; Protein Transport; Receptors, Cell Surface/metabolism; Trans-Activators

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:APBB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99MK2

F

Seeded From UniProt

complete

RAT:APBB1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:APBB1

involved_in

GO:0006302: double-strand break repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:APBB1

involved_in

GO:0045739: positive regulation of DNA repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:APBB1

involved_in

GO:0043967: histone H4 acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:KAT5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46933

F

Seeded From UniProt

complete

RAT:KAT5

enables

GO:0004402: histone acetyltransferase activity

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

RAT:KAT5

involved_in

GO:0043967: histone H4 acetylation

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete


See also

References

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