leads to Cdc48 recruitment for extraction and
degradation of the incomplete translation product.
Rqc2p, through specific binding to Ala(IGC) and
Thr(IGU) tRNAs, directs the template-free and
40S-free elongation of the incomplete translation product with CAT tails. CAT tails induce a
heat shock response through a mechanism that
is yet to be determined.
Hypomorphic mutations in the mammalian
homolog of LTN1 cause neurodegeneration in
mice ( 21). Similarly, mice with mutations in a central nervous system–specific isoform of tRNAArg
and GTPBP2, a homolog of yeast Hbs1 which
works with PELOTA/Dom34 to dissociate stalled
80S ribosomes, suffer from neurodegeneration
( 22). These observations reveal the consequences
that ribosome stalls impose on the cellular economy. Eubacteria rescue stalled ribosomes with
the transfer-messenger RNA (tmRNA)–SmpB system, which appends nascent chains with a unique
C-terminal tag that targets the incomplete protein product for proteolysis ( 23). The mechanisms
used by eukaryotes, which lack tmRNA, to recognize and rescue stalled ribosomes and their
incomplete translation products have been unclear. The RQC—and Rqc2p’s CAT tail tagging
mechanism in particular—bear both similarities
and contrasts to the tmRNA trans-translation
system. The evolutionary convergence upon distinct mechanisms for extending incomplete nascent chains at the C terminus argues for their
importance in maintaining proteostasis. One advantage of tagging stalled chains is that it may
distinguish them from normal translation products
and facilitate their removal from the protein pool.
An alternate, not mutually exclusive, possibility
is that the extension serves to test the functional
integrity of large ribosomal subunits, so that the
cell can detect and dispose of defective large subunits that induce stalling.
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Electron microscopy was performed at the University of Utah and
the University of California. We thank D. Belnap (University of
Utah) and M. Braunfeld (University of California, San Francisco) for
supervision of the electron microscopes; A. Orendt and the Utah
Center for High Performance Computing and the NSF Extreme
Science and Engineering Discovery Environment consortium for
computational support; D. Sidote (University of Texas at Austin)
for help processing RNA-seq data; and D. Herschlag and
P. Harbury for helpful comments. Amino acid analysis was
performed by J. Shulze at the University of California, Davis
Proteomics Core. Edman sequencing was performed at Stanford
University’s Protein and Nucleic Acid Facility by D. Winant. This
work was supported by the Searle Scholars Program (A.F.);
Stanford University (O.B.); NIH grants 1DP2GM110772-01 (A.F.),
GM37949, and GM37951 (A.M.L.); the Center for RNA Systems
Biology grants P50 GM102706 (J.S. W.) and U01 GM098254
(J.S. W.); and the Howard Hughes Medical Institute (J.S. W.).
The authors declare no competing financial interests. The
cryo-EM structures have been deposited at the Electron
Microscopy Data Bank (accession codes 2811, 2812, 6169, 6170,
6171, 6172, 6176, and 6201).
Materials and Methods
Figs. S1 to S13
References ( 27–41)
7 August 2014; accepted 14 November 2014
Variation in cancer risk among
tissues can be explained by the
number of stem cell divisions
Cristian Tomasetti1 and Bert Vogelstein2*
Some tissue types give rise to human cancers millions of times more often than other
tissue types. Although this has been recognized for more than a century, it has never been
explained. Here, we show that the lifetime risk of cancers of many different types is strongly
correlated (0.81) with the total number of divisions of the normal self-renewing cells
maintaining that tissue’s homeostasis. These results suggest that only a third of the variation
in cancer risk among tissues is attributable to environmental factors or inherited
predispositions. The majority is due to “bad luck,” that is, random mutations arising during
DNA replication in normal, noncancerous stem cells. This is important not only for
understanding the disease but also for designing strategies to limit the mortality it causes.
Extreme variation in cancer incidence across different tissues is well known; for exam- ple, the lifetime risk of being diagnosed with cancer is 6.9% for lung, 1.08% for thyroid, 0.6% for brain and the rest of the
nervous system, 0.003% for pelvic bone and
0.00072% for laryngeal cartilage (1– 3). Some of
these differences are associated with well-known
risk factors such as smoking, alcohol use, ultraviolet light, or human papilloma virus (HPV)
( 4, 5), but this applies only to specific populations
exposed to potent mutagens or viruses. And such
exposures cannot explain why cancer risk in
tissues within the alimentary tract can differ by
as much as a factor of 24 [esophagus (0.51%),
large intestine ( 4.82%), small intestine (0.20%),
and stomach (0.86%)] ( 3). Moreover, cancers of
the small intestinal epithelium are three times
less common than brain tumors ( 3), even though
small intestinal epithelial cells are exposed to
much higher levels of environmental mutagens
than are cells within the brain, which are pro-
tected by the blood-brain barrier.
Another well-studied contributor to cancer is
inherited genetic variation. However, only 5 to
10% of cancers have a heritable component
( 6–8), and even when hereditary factors in predisposed individuals can be identified, the way in
which these factors contribute to differences in
cancer incidences among different organs is
obscure. For example, the same, inherited mutant
APC gene is responsible for both the predisposition to colorectal and small intestinal cancers
1Division of Biostatistics and Bioinformatics, Department of
Oncology, Sidney Kimmel Cancer Center, Johns Hopkins
University School of Medicine and Department of
Biostatistics, Johns Hopkins Bloomberg School of Public
Health, 550 North Broadway, Baltimore, MD 21205, USA.
2Ludwig Center for Cancer Genetics and Therapeutics
and Howard Hughes Medical Institute, Johns Hopkins
Kimmel Cancer Center, 1650 Orleans Street, Baltimore,
MD 21205, USA.
*Corresponding author. E-mail: firstname.lastname@example.org (C. T.);