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Caspase cleavage-mediated substrate change: switching function of Dicer between RNAi pathway and apoptosis pathway

written by cail • posted in Theory • 2,001 views • no comments

As in NATURE, everything is possible! This is what I felt when I saw the following paper.

Science. 2010 Mar 11. [Epub ahead of print]

Caspase-Dependent Conversion of Dicer Ribonuclease into a Death-Promoting Deoxyribonuclease.

Nakagawa A, Shi Y, Kage-Nakadai E, Mitani S, Xue D.

Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.

Chromosome fragmentation is a hallmark of apoptosis, conserved in diverse organisms. In mammals, caspases activate apoptotic chromosome fragmentation by cleaving and inactivating an apoptotic nuclease inhibitor. We report that inactivation of the Caenorhabditis elegans dcr-1 gene, which encodes the Dicer ribonuclease important for processing of small RNAs, compromises apoptosis and blocks apoptotic chromosome fragmentation. DCR-1 was cleaved by the CED-3 caspase to generate a C-terminal fragment with deoxyribonuclease activity, which produced 3' hydroxyl DNA breaks on chromosomes and promoted apoptosis. Thus, caspase-mediated activation of apoptotic DNA degradation is conserved. DCR-1 functions in fragmenting chromosomal DNA during apoptosis, in addition to processing of small RNAs, and undergoes a protease-mediated conversion from a ribonuclease to a deoxyribonuclease.

PMID: 20223951

"Our findings that C. elegans DCR-1 is involved in generating TUNEL-reactive DNA breaks in apoptotic cells that are later resolved by downstream apoptotic nucleases such as CPS-6 and NUC-1 and that DCR-1 promotes, and even is required for, apoptosis in sensitized genetic backgrounds reveal an unexpected role of DCR-1 in apoptosis and in initiating apoptotic DNA degradation."

"The proteolytic mechanism we discovered, through which a ribonuclease is disabled and converted into a DNase, may have more general implications on regulation of RNases and DNases, RNA and DNA binding proteins, and their associated cellular functions."

As stated in the F1000 review: "It is of interest to see 1) if this interplay between the small RNA processing pathway and the apoptosis pathway is conserved in mammals and 2) if this cleavage-mediated substrate change can be found in other nucleases."