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Overexpression of Helicard, a CARD-Containing Helicase Cleaved during Apoptosis, Accelerates DNA Degradation

2002; Elsevier BV; Volume: 12; Issue: 10 Linguagem: Inglês

10.1016/s0960-9822(02)00842-4

1879-0445

Magdalena Kovacsovics, Fabio Martinon, Olivier Micheau, Jean-Luc Bodmer, Kay Hofmann, Jürg Tschopp,

Metabolism and Genetic Disorders

Apoptotic cell death is characterized by several morphological nuclear changes, such as chromatin condensation and extensive fragmentation of chromosomal DNA [1Nagata S. Apoptotic DNA fragmentation.Exp. Cell Res. 2000; 256: 12-18Crossref PubMed Scopus (712) Google Scholar]. These alterations are primarily triggered through the activation of caspases, which subsequently cleave nuclear substrates. Caspase-3 induces processing of Acinus, which leads to chromatin condensation [2Sahara S. Aoto M. Eguchi Y. Imamoto N. Yoneda Y. Tsujimoto Y. Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation.Nature. 1999; 401: 168-173Crossref PubMed Scopus (368) Google Scholar]. DNA fragmentation is dependent on the DNase CAD, which is released from its inhibitor, ICAD, upon cleavage by caspase-3 [3Sakahira H. Enari M. Nagata S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis.Nature. 1998; 391: 96-99Crossref PubMed Scopus (1395) Google Scholar]. DNA degradation is also induced by AIF [4Susin S.A. Lorenzo H.K. Zamzami N. Marzo I. Snow B.E. Brothers G.M. Mangion J. Jacotot E. Costantini P. Loeffler M. et al.Molecular characterization of mitochondrial apoptosis-inducing factor.Nature. 1999; 397: 441-446Crossref PubMed Scopus (3376) Google Scholar] and endonuclease G [5Li L.Y. Luo X. Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria.Nature. 2001; 412: 95-99Crossref PubMed Scopus (1345) Google Scholar, 6Parrish J. Li L. Klotz K. Ledwich D. Wang X. Xue D. Mitochondrial endonuclease G is important for apoptosis in C. elegans.Nature. 2001; 412: 90-94Crossref PubMed Scopus (346) Google Scholar], which are both released from mitochondria upon death stimuli but do not require prior processing by caspases for their DNase activity. Here we report the identification of a widely expressed helicase designated Helicard, which contains two N-terminal CARD domains and a C-terminal helicase domain. Upon apoptotic stimuli, Helicard is cleaved by caspases, thereby separating the CARD domains from the helicase domain. While Helicard localizes in the cytoplasm, the helicase-containing fragment is found in the nucleus. Helicard accelerates Fas ligand-mediated DNA degradation, whereas a noncleavable or a helicase-dead Helicard mutant does not, implicating Helicard in the nuclear remodeling occurring during apoptosis.