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

Radek Szklarczyk, Jaap Heringa, Sergei Kosakovsky Pond, Anton Nekrutenko

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12807-12812
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number31
DOIs
StatePublished - Jul 31 2007

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Exons
Neoplasms
Reading Frames
Mutation
Alternative Splicing
Open Reading Frames
Carcinogenesis
Proteins
Amino Acids
Costs and Cost Analysis
Genes
Conflict (Psychology)
Drive

All Science Journal Classification (ASJC) codes

  • General

Cite this

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abstract = "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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Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function. / Szklarczyk, Radek; Heringa, Jaap; Pond, Sergei Kosakovsky; Nekrutenko, Anton.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 31, 31.07.2007, p. 12807-12812.

Research output: Contribution to journalArticle

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