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Molecular and Cellular Biology, October 2007, p. 7063-7072, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00769-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Species Selectivity of Mixed-Lineage Leukemia/Trithorax and HCF Proteolytic Maturation Pathways{triangledown}

Francesca Capotosti,1 James J.-D. Hsieh,2 and Winship Herr1*

Center for Integrative Genomics, University of Lausanne, Génopode Building, 1015 Lausanne, Switzerland,1 Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 631102

Received 2 May 2007/ Returned for modification 15 June 2007/ Accepted 27 July 2007

Site-specific proteolytic processing plays important roles in the regulation of cellular activities. The histone modification activity of the human trithorax group mixed-lineage leukemia (MLL) protein and the cell cycle regulatory activity of the cell proliferation factor herpes simplex virus host cell factor 1 (HCF-1) are stimulated by cleavage of precursors that generates stable heterodimeric complexes. MLL is processed by a protease called taspase 1, whereas the precise mechanisms of HCF-1 maturation are unclear, although they are known to depend on a series of sequence repeats called HCF-1PRO repeats. We demonstrate here that the Drosophila homologs of MLL and HCF-1, called Trithorax and dHCF, are both cleaved by Drosophila taspase 1. Although highly related, the human and Drosophila taspase 1 proteins display cognate species specificity. Thus, human taspase 1 preferentially cleaves MLL and Drosophila taspase 1 preferentially cleaves Trithorax, consistent with coevolution of taspase 1 and MLL/Trithorax proteins. HCF proteins display even greater species-specific divergence in processing: whereas dHCF is cleaved by the Drosophila taspase 1, human and mouse HCF-1 maturation is taspase 1 independent. Instead, human and Xenopus HCF-1PRO repeats are cleaved in vitro by a human proteolytic activity with novel properties. Thus, from insects to humans, HCF proteins have conserved proteolytic maturation but evolved different mechanisms.

* Corresponding author. Mailing address: Center for Integrative Genomics, University of Lausanne, Génopode Building, 1015 Lausanne, Switzerland. Phone: 41-21-692-39-22. Fax: 41-21-692-39-25. E-mail: winship.herr{at}unil.ch

{triangledown} Published ahead of print on 13 August 2007.

Molecular and Cellular Biology, October 2007, p. 7063-7072, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00769-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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