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Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12807-12. Epub 2007 Jul 24.

Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function.

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Centre for Integrative Bioinformatics, Vrije University, De Boelelaan 1081a, 1081 HV Amsterdam, The Netherlands.


INK4a/ARF tumor suppressor locus encodes two protein products, INK4a and ARF, essential for controlling tumorigenesis and mutated in more than half of human cancers. There is no resemblance between the two proteins: their coding regions are assembled by alternative splicing of two mutually exclusive 5' exons into a constitutive one containing overlapping out-of-phase reading frames. We show that the dual-coding arrangement conflicts with the high cost of mutations within INK4a/ARF. Unexpectedly, the locus evolves rapidly and asymmetrically, with ARF accumulating the majority of amino acid replacements. Rapid evolution drives both INK4a and ARF proteins out of sync with other members of the RB and p53 tumor suppressor pathways, both of which are controlled by the locus. Yet, the asymmetric behavior may be an intrinsic property of dual-coding exons: INK4a/ARF closely mimics the evolution of 90 newly identified genes with similar dual-coding structure. Thus, the strong link between mutations in INK4a/ARF and cancer may be a direct consequence of the architecture of the locus.

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