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J. Biol. Chem., Vol. 277, Issue 19, 16775-16781, May 10, 2002
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From the Caspases are a conserved family of proteases that
play a critical role in the execution of apoptosis by cleaving key
cellular proteins at Asp residues and modifying their function. Using
an expression cloning strategy we recently developed, we isolated human
RAD21/SCC1/MCD1 as a novel caspase substrate. RAD21 is a component of
the cohesin complex that holds sister chromatids together during
mitosis and repairs double-strand DNA breaks. Interestingly, RAD21 is
cleaved by a caspase-like Esp1/separase at the onset of anaphase to
trigger sister chromatid separation. Here, we demonstrate that human
RAD21 is preferentially cleaved at Asp279 by
caspases-3 and -7 in vitro to generate two major
proteolytic products of ~65 and 48 kDa. Moreover, we show that RAD21
is specifically proteolyzed by caspases into a similarly sized
65-kDa carboxyl-terminal product in cells undergoing apoptosis in
response to diverse stimuli. We also demonstrate that caspase
proteolysis of RAD21 precedes apoptotic chromatin condensation and has
important functional consequences, viz. the partial removal
of RAD21 from chromatin and the production of a proapoptotic
carboxyl-terminal cleavage product that amplifies the cell death
signal. Taken together, these findings point to an entirely novel
function of RAD21 in the execution of apoptosis.
Caspase Proteolysis of the Cohesin Component RAD21 Promotes
Apoptosis*
,,,,¶
Robert H. Lurie Comprehensive Cancer Center
and the Department of Medicine, Northwestern University Medical School,
Chicago, IL 60611 and the § Peter MacCallum Cancer
Institute, Melbourne 8006, Australia
*
This work was supported in part by Grant DAMD 17-00-1-0096 from the Department of Defense Prostate Cancer Research Program, by
National Institutes of Health grants NS31957 (to V. L. C.), T32-CA79447 (to M. M.), and 5T32-CA70085 (to M. K.), by a
grant from the National Health and Medical Research Council Australia (to M. J. M.), by institutional research grants to Northwestern University from the Howard Hughes Medical Institute and the American Cancer Society (to V. L. C.), and by the Elizabeth Boughton Trust (to
V. L. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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