Identification of a Novel Interaction between Menin and the PAF Complex

Abstract

<p>Multiple Endocrine Neoplasia Type 1 (MEN1) is an inherited cancer syndrome characterized by tumour formation in two or more endocrine tissues. Tumours arise due to a biallelic loss of the <em>MEN1</em> tumour suppressor gene, consistent with the "two hit" loss of function, in which the first "hit" occurs in the germline and the second in somatic cells. <em>MEN1</em> encodes a 67kDa protein, menin, which functions in a variety of cellular processes including transcription regulation, cell cycle control and genome stability. The <em>Drosophila melanogaster</em> homolog of menin is an 83kDa protein sharing many of the amino acids that routinely exhibit mutations in MEN1 patients. To identify novel menininteracting proteins, a mass spectrum analysis was performed and Atu was identified. Atu (dLeo1) is the <em>Drosophila melanogaster</em> homolog of Leo1 , a member of the RNA Polymerase II associated factor (PAF) complex. PAF functions as a platform in transcription elongation, recruiting proteins to RNA Polymerase II facilitating such processes as histone modification, 3' end formation and mRNA surveillance. Studies were undertaken to verify the interaction between menin and dLeo1 in the <em>Drosophila melanogaster</em> model system, and determine the role of the interaction in maintaining genome stability in response to stress. The menin-dLeo1 interaction was confirmed, observed following non-genotoxic stress. dLeo1 and dPaf1 , and additional member of PAF, were in turn found to play a role in maintaining genome stability. Loss of dLeo1 in particular results in increased genome instability even under physiological conditions. Thus a novel menin-interacting protein was identified, which in turn will contribute to the understanding of menin as a tumour suppressor.</p>