TY - JOUR
T1 - Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function
AU - Szklarczyk, Radek
AU - Heringa, Jaap
AU - Pond, Sergei Kosakovsky
AU - Nekrutenko, Anton
PY - 2007/7/31
Y1 - 2007/7/31
N2 - 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.
AB - 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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U2 - 10.1073/pnas.0703238104
DO - 10.1073/pnas.0703238104
M3 - Article
C2 - 17652172
AN - SCOPUS:34547895882
SN - 0027-8424
VL - 104
SP - 12807
EP - 12812
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -