A new effector pathway links ATM kinase with the DNA damage response.

TY - JOUR

T1 - A new effector pathway links ATM kinase with the DNA damage response.

AU - Demonacos, Constantinos

AU - Krstic-Demonacos, Marija

AU - Smith, Linda

AU - Xu, Danmei

AU - O'Connor, Darran P

AU - Jansson, Martin

AU - La Thangue, Nicholas B

N1 - Keywords: Antibodies, Monoclonal; Carrier Proteins; Cell Cycle Proteins; Cell Extracts; Cell Line, Tumor; Cell Nucleus; Cytoplasm; DNA Damage; DNA-Binding Proteins; Flow Cytometry; Fluorescent Antibody Technique, Direct; Humans; Mutation; Phosphorylation; Precipitin Tests; Protein-Serine-Threonine Kinases; RNA, Small Interfering; Serine; Tumor Suppressor Proteins

PY - 2004

Y1 - 2004

N2 - The related kinases ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) phosphorylate a limited number of downstream protein targets in response to DNA damage. Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap.

AB - The related kinases ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) phosphorylate a limited number of downstream protein targets in response to DNA damage. Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap.

U2 - 10.1038/ncb1170

DO - 10.1038/ncb1170

M3 - Journal article

C2 - 15448695

SN - 1465-7392

VL - 6

SP - 968

EP - 976

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 10

ER -