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Molecular and Cellular Biology, December 2002, p. 8267-8277, Vol. 22, No. 23
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.23.8267-8277.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Linking Sister Chromatid Cohesion and Apoptosis: Role of Rad21

Debananda Pati,* Nenggang Zhang, and Sharon E. Plon

Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030

Received 9 May 2002/ Accepted 9 September 2002

Rad21 is one of the major cohesin subunits that holds sister chromatids together until anaphase, when proteolytic cleavage by separase, a caspase-like enzyme, allows chromosomal separation. We show that cleavage of human Rad21 (hRad21) also occurs during apoptosis induced by diverse stimuli. Induction of apoptosis in multiple human cell lines results in the early (4 h after insult) generation of 64- and 60-kDa carboxy-terminal hRad21 cleavage products. We biochemically mapped an apoptotic cleavage site at residue Asp-279 (D279) of hRad21. This apoptotic cleavage site is distinct from previously described mitotic cleavage sites. hRad21 is a nuclear protein; however, the cleaved 64-kDa carboxy-terminal product is translocated to the cytoplasm early in apoptosis before chromatin condensation and nuclear fragmentation. Overexpression of the 64-kDa cleavage product results in apoptosis in Molt4, MCF-7, and 293T cells, as determined by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) and Annexin V staining, assaying of caspase-3 activity, and examination of nuclear morphology. Given the role of hRad21 in chromosome cohesion, the cleaved C-terminal product and its translocation to the cytoplasm may act as a nuclear signal for apoptosis. In summary, we show that cleavage of a cohesion protein and translocation of the C-terminal cleavage product to the cytoplasm are early events in the apoptotic pathway and cause amplification of the cell death signal in a positive-feedback manner.

* Corresponding author. Mailing address: Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin St., MC 3-3320, Houston, TX 77030. Phone: (832) 824-4575. Fax: (832) 825-4202. E-mail: pati{at}bcm.tmc.edu.

Molecular and Cellular Biology, December 2002, p. 8267-8277, Vol. 22, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.23.8267-8277.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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