p8/nupr1 regulates DNA-repair activity after double-strand gamma irradiation-induced DNA damage.
The stress protein p8 is a small, highly basic, unfolded, and multifunctional protein. We have previously shown that most of its functions are exerted through interactions with other proteins, whose activities are thereby enhanced or repressed. In this work we describe another example of such mechanism, by which p8 binds and negatively regulates MSL1, a histone acetyl transferase (HAT)-associated protein, which in turn binds the DNA-damage-associated 53BP1 protein to facilitate DNA repair following DNA gamma-irradiation. Contrary to the HAT-associated activity, MSL1-dependent DNA-repair activity is almost completely dependent on 53BP1 expression. The picture that has emerged from our findings is that 53BP1 could be a scaffold that gets the HAT MSL1-dependent DNA-repair activity to the sites of DNA damage. Finally, we also found that, although p8 expression is transiently activated after gamma-irradiation, it is eventually submitted to sustained down-regulation, presumably to allow development of MSL1-associated DNA-repair activity. We conclude that interaction of MSL1 with 53BP1 brings MSL1-dependent HAT activity to the vicinity of damaged DNA. MSL1-dependent HAT activity, which is negatively regulated by the stress protein p8, induces chromatin remodeling and relaxation allowing access to DNA of the repair machinery.
Gironella
Meritxell
M
INSERM U.624, Stress Cellulaire, Case 915, Parc Scientifique et Technologique de Luminy, Marseille Cedex 9, France.
Malicet
Cedric
C
Cano
Carla
C
Sandi
Maria José
MJ
Hamidi
Tewfik
T
Tauil
Ricardo Martin Neme
RM
Baston
Mariela
M
Valaco
Pia
P
Moreno
Silvia
S
Lopez
Frederic
F
Neira
Jose Luis
JL
Dagorn
Jean Charles
JC
Iovanna
Juan Lucio
JL
D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004260:DNA Repair / Q000502:physiology*; D005720:Gamma Rays; D015870:Gene Expression / Q000235:genetics / Q000528:radiation effects; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1; D020798:Two-Hybrid System Techniques
D051792:Basic Helix-Loop-Helix Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C491643:NUPR1 protein, human; C498301:TP53BP1 protein, human; C544740:MSL1 protein, human