RESUMO
ADP-ribosylation is a dynamic post-translation modification that regulates the early phase of various DNA repair pathways by recruiting repair factors to chromatin. ADP-ribosylation levels are defined by the activities of specific transferases and hydrolases. However, except for the transferase PARP1/ARDT1 little is known about regulation of these enzymes. We found that MacroD2, a mono-ADP-ribosylhydrolase, is exported from the nucleus upon DNA damage, and that this nuclear export is induced by ATM activity. We show that the export is dependent on the phosphorylation of two SQ/TQ motifs, suggesting a novel direct interaction between ATM and ADP-ribosylation. Lastly, we show that MacroD2 nuclear export temporally restricts its recruitment to DNA lesions, which may decrease the net ADP-ribosylhydrolase activity at the site of DNA damage. Together, our results identify a novel feedback regulation between two crucial DNA damage-induced signaling pathways: ADP-ribosylation and ATM activation.
Assuntos
Difosfato de Adenosina/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Dano ao DNA , Enzimas Reparadoras do DNA/genética , Hidrolases/genética , Poli(ADP-Ribose) Polimerases/genética , Processamento de Proteína Pós-Traducional , Transporte Ativo do Núcleo Celular , Motivos de Aminoácidos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Retroalimentação Fisiológica , Células HeLa , Humanos , Hidrolases/metabolismo , Osteoblastos , Fosforilação , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de SinaisRESUMO
The modification of serines by molecules of ADP-ribose plays an important role in signaling that the DNA in a cell has been damaged and needs to be repaired.