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A novel mechanism underlies caspase-dependent conversion of the dicer ribonuclease into a deoxyribonuclease during apoptosis.

ABSTRACT: During C. elegans apoptosis, the dicer ribonuclease (DCR-1) is cleaved by the cell death protease CED-3 to generate a truncated DCR-1 (tDCR-1) with one and a half ribonuclease III (RNase III) domains, converting it into a deoxyribonuclease (DNase) that initiates apoptotic chromosome fragmentation. We performed biochemical and functional analyses to understand this unexpected RNase to DNase conversion. In full-length DCR-1, tDCR-1 DNase activity is suppressed by its N-terminal DCR-1 sequence. However, not all the sequence elements in the N-terminal DCR-1 are required for this suppression. Our deletion analysis reveals that a 20-residue ?-helix sequence in DCR-1 appears to define a critical break point for the sequence required for suppressing tDCR-1 DNase activity through a structure-dependent mechanism. Removal of the N-terminal DCR-1 sequence from tDCR-1 activates a DNA-binding activity that also requires the one half RNase IIIa domain, and enables tDCR-1 to process DNA. Consistently, structural modeling of DCR-1 and tDCR-1 suggests that cleavage of DCR-1 by CED-3 may cause a conformational change that allows tDCR-1 to bind and process DNA, and may remove steric hindrance that blocks DNA access to tDCR-1. Moreover, a new DNase can be engineered using different RNase III domains, including the one from bacterial RNase III. Our results indicate that very distantly related RNase III enzymes have the potential to cleave DNA when processed proteolytically or paired with an appropriate partner that facilitates binding to DNA. We suggest the possibility that this phenomenon may be extrapolated to other ribonucleases.

SUBMITTER: Ge X

PROVIDER: S-EPMC3915905 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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A novel mechanism underlies caspase-dependent conversion of the dicer ribonuclease into a deoxyribonuclease during apoptosis.

Ge Xiao X Zhao Xiang X Nakagawa Akihisa A Gong Xinqi X Skeen-Gaar Riley Robert RR Shi Yong Y Gong Haipeng H Wang Xinquan X Xue Ding D

Cell research 20131210 2

During C. elegans apoptosis, the dicer ribonuclease (DCR-1) is cleaved by the cell death protease CED-3 to generate a truncated DCR-1 (tDCR-1) with one and a half ribonuclease III (RNase III) domains, converting it into a deoxyribonuclease (DNase) that initiates apoptotic chromosome fragmentation. We performed biochemical and functional analyses to understand this unexpected RNase to DNase conversion. In full-length DCR-1, tDCR-1 DNase activity is suppressed by its N-terminal DCR-1 sequence. How ...[more]

PMID: 24323044

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Project description:Gene expression dictates fundamental cellular processes and its de-regulation leads to pathological conditions. A key contributor to the fine-tuning of gene expression is Dicer, an RNA-binding protein (RBPs) that forms complexes and affects transcription by acting at the post-transcriptional level via the targeting of mRNAs by Dicer-produced small non-coding RNAs. This review aims to present the contribution of Dicer protein in a wide spectrum of human pathological conditions, including cancer, neurological, autoimmune, reproductive and cardiovascular diseases, as well as viral infections. Germline mutations of Dicer have been linked to Dicer1 syndrome, a rare genetic disorder that predisposes to the development of both benign and malignant tumors, but the exact correlation of Dicer protein expression within the different cancer types is unclear, and there are contradictions in the data. Downregulation of Dicer is related to Geographic atrophy (GA), a severe eye-disease that is a leading cause of blindness in industrialized countries, as well as to psychiatric and neurological diseases such as depression and Parkinson's disease, respectively. Both loss and upregulation of Dicer protein expression is implicated in severe autoimmune disorders, including psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis and autoimmune thyroid diseases. Loss of Dicer contributes to cardiovascular diseases and causes defective germ cell differentiation and reproductive system abnormalities in both sexes. Dicer can also act as a strong antiviral with a crucial role in RNA-based antiviral immunity. In conclusion, Dicer is an essential enzyme for the maintenance of physiology due to its pivotal role in several cellular processes, and its loss or aberrant expression contributes to the development of severe human diseases. Further exploitation is required for the development of novel, more effective Dicer-based diagnostic and therapeutic strategies, with the goal of new clinical benefits and better quality of life for patients.

Dataset Information

A novel mechanism underlies caspase-dependent conversion of the dicer ribonuclease into a deoxyribonuclease during apoptosis.

Publications

A novel mechanism underlies caspase-dependent conversion of the dicer ribonuclease into a deoxyribonuclease during apoptosis.

Similar Datasets

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