Identification of Novel Interaction Partners of Ets-1: Focus on DNA Repair

Abstract

The transcription factor Ets-1 (ETS proto-oncogene 1) shows low expression levels except in specific biological processes like haematopoiesis or angiogenesis. Elevated levels of expression are observed in tumor progression, resulting in Ets-1 being named an oncoprotein. It has recently been shown that Ets-1 interacts with two DNA repair enzymes, PARP-1 (poly(ADP-ribose) polymerase 1) and DNA-PK (DNA-dependent protein kinase), through two different domains and that these interactions play a role in cancer. Considering that Ets-1 can bind to distinctly different domains of two DNA repair enzymes, we hypothesized that the interaction can be transposed onto homologs of the respective domains. We have searched for sequence and structure homologs of the interacting ETS(Ets-1), BRCT(PARP-1) and SAP(DNA-PK) domains, and have identified several candidate binding pairs that are currently not annotated as such. Many of the Ets-1 partners are associated to DNA repair mechanisms. We have applied protein-protein docking to establish putative interaction poses and investigated these using centrality analyses at the protein residue level. Most of the identified poses are virtually similar to our recently established interaction model for Ets-1/PARP-1 and Ets-1/DNA-PK. Our work illustrates the potentially high number of interactors of Ets-1, in particular involved in DNA repair mechanisms, which shows the oncoprotein as a potential important regulator of the mechanism.

BRCT Domains: Structure, Functions, and Implications in Disease—New Therapeutic Targets for Innovative Drug Discovery against Infections

“…The interaction of BRCT domain of PARP-1 with Ets-1, a transcription factor whose activity is involved in numerous cellular mechanisms, including angiogenesis, apoptosis, and tumour invasion [ 128 ], has also been reported. In a later study, using a protein-protein docking in silico method, Brysbaert et al described BRCT homologs which potentially interacted with the oncoprotein Ets-1 and identified putative binding pairs associated with DNA repair mechanisms [ 129 ]. Similarly, the abovementioned drug-like inhibitor Bractoppin was detected via a fluorescence polarization assay, followed by in silico docking and Structure-Activity Relationships [ 115 ], reinforcing the advantages of these techniques in drug development.…”