Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Usluer, S; Galhuber, M; Khanna, Y; Bourgeois, B; Spreitzer, E; Michenthaler, H; Prokesch, A; Madl, T.
Disordered regions mediate the interaction of p53 and MRE11.
Biochim Biophys Acta Mol Cell Res. 2023; 1871(2): 119654
Doi: 10.1016/j.bbamcr.2023.119654
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PubMed
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- Führende Autor*innen der Med Uni Graz
- Madl Tobias
- Usluer Sinem
- Co-Autor*innen der Med Uni Graz
- Bourgeois Benjamin Michel Rene
- Galhuber Markus
- Khanna Yukti
- Michenthaler Helene
- Prokesch Andreas
- Spreitzer Emil
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- Abstract:
- The genome is frequently targeted by genotoxic agents, resulting in the formation of DNA scars. However, cells employ diverse repair mechanisms to restore DNA integrity. Among these processes, the Mre11-Rad50-Nbs1 complex detects double-strand breaks (DSBs) and recruits DNA damage response proteins such as ataxia-telangiectasia-mutated (ATM) kinase to DNA damage sites. ATM phosphorylates the transactivation domain (TAD) of the p53 tumor suppressor, which in turn regulates DNA repair, growth arrest, apoptosis, and senescence following DNA damage. The disordered glycine-arginine-rich (GAR) domain of double-strand break protein MRE11 (MRE11GAR) and its methylation are important for DSB repair, and localization to Promyelocytic leukemia nuclear bodies (PML-NBs). There is preliminary evidence that p53, PML protein, and MRE11 might co-localize and interact at DSB sites. To uncover the molecular details of these interactions, we aimed to identify the domains mediating the p53-MRE11 interaction and to elucidate the regulation of the p53-MRE11 interaction by post-translational modifications (PTMs) through a combination of biophysical techniques. We discovered that, in vitro, p53 binds directly to MRE11GAR mainly through p53TAD2 and that phosphorylation further enhances this interaction. Furthermore, we found that MRE11GAR methylation still allows for binding to p53. Overall, we demonstrated that p53 and MRE11 interaction is facilitated by disordered regions. We provide for the first time insight into the molecular details of the p53-MRE11 complex formation and elucidate potential regulatory mechanisms that will promote our understanding of the DNA damage response. Our findings suggest that PTMs regulate the p53-MRE11 interaction and subsequently their colocalization to PML-NBs upon DNA damage.
- Find related publications in this database (Keywords)
- Intrinsically disordered proteins
- NMR spectroscopy
- Biophysical interaction assays
- Phosphorylation
- Arginine methylation