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Investigating the Role of a Dual Motif in DNA Binding by PAX3‐FOXO1
Author(s) -
Weatherspoon Amber,
Evans Ronise,
Cherlin Tess,
Bratton Melyssa,
Johanson Kelly
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.912.3
Subject(s) - pax3 , alveolar rhabdomyosarcoma , transcription factor , foxo1 , fusion gene , biology , gene , fusion protein , cancer research , genetics , rhabdomyosarcoma , binding site , computational biology , medicine , sarcoma , recombinant dna , pathology
Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma that can be divided into two main categories. Embryonal Rhabdomyosarcoma (ERMS) usually affects children in the first five years of life and has not been linked to the presence of specific gene fusions. Alveolar Rhabdomyosarcoma (ARMS), which is more aggressive, typically affects all age groups equally but a larger portion of RMS occur in older children. The more aggressive form of ARMS is primarily characterized by a reciprocal (2;13) (q35; q14) translocation, which results in the fusion of the N‐terminus of PAX3 and the C‐terminus of FOXO1. PAX3‐FOXO1 mediated gene activation leads to ARMS development has been linked to several events involved in ARMS development, although all targets of this fusion protein have not been identified. A search of an updated ChIP‐seq screen of 3881 PAX3‐FOXO1 putative binding sites revealed that 36% contained both a PAX3 paired domain and FOXO1 recognition sequence within proximity. In vitro examination of a PAX3‐FOXO1 dual motif indicates that mutation of the FOXO1 site or residues in the FOXO1 DNA‐binding domain affect both binding and activation of these sequences. Binding sites for other transcription factors overlap or surround several of these dual motifs, indicating the need to examine potential transcriptional complexes formed by PAX3‐FOXO1. Understanding the binding specificities and activities of this fusion protein will allow for a better understanding of the transcription factor which may lead to future therapeutic remedies. Support or Funding Information NIH BUILD RL5GM118966‐02, NIH RCMI 2G12MD007595‐06, NIH BUILD TL4GM118968