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RNA decay: a novel therapeutic target in bacteria

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Abstract The need for novel antibiotics is greater now than perhaps any time since the pre‐antibiotic era. Indeed, the recent collapse of most pharmaceutical antibacterial groups, combined with the emergence of hypervirulent and pan‐antibiotic‐resistant bacteria have, in effect, created a ‘perfect storm’ that has severely compromised infection treatment options and led to dramatic increases in the incidence and severity of bacterial infections. To put simply, it is imperative that we develop new classes of antibiotics for the therapeutic intervention of bacterial infections. In that regard, RNA degradation is an essential biological process that has not been exploited for antibiotic development. Herein we discuss the factors that govern bacterial RNA degradation, highlight members of this machinery that represent attractive antimicrobial drug development targets and describe the use of high‐throughput screening as a means of developing antimicrobials that target these enzymes. Such agents would represent first‐in‐class antibiotics that would be less apt to inactivation by currently encountered enzymatic antibiotic‐resistance determinants. WIREs RNA 2012, 3:443–454. doi: 10.1002/wrna.1110 This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA in Disease and Development > RNA in Disease

Mechanisms of mRNA decay. (a) Model of mRNA degradosome and degradation pathways in Escherichia coli. The E. coli degradosome includes RNA helicase B (RhlB), enolase, polynucleotide phosphorylase (PNPase), and RNase E. Initiation of mRNA decay occurs with the internal cleavage by RNase E. This cleavage favors 5′ monophosphorylated transcripts, which is achieved through the action of RppH. Degradosome‐independent endoribonucleases RNase G, RNase P, and RNase I cleave single‐stranded RNA (ssRNA), while RNase III recognizes and cleaves double‐stranded RNA secondary structures (dsRNA). Resulting cleavage products are further digested by the degradosome PNPase or by the action of RNase R and RNase II in a 3′ 5′ manner into fragments that are degraded into single nucleotides by the 3′ 5′ endoribonuclease Orn. (b) Proposed model of mRNA degradosome‐like complex in Staphylococcus aureus. The Gram‐positive degradosome‐like complex includes RNase J1, RNase J2, RNase Y (also known as CvfA and YmdA), enolase, RNA helicase (CshA), PNPase, phosphofructokinase (Pfk), and RnpA. In Gram‐positive bacteria, internal cleavage by RNase J1 initiates mRNA degradation. RNase J1 preferentially cleaves 5′ monophosphorylated mRNA molecules that have been stripped of pyrophosphate by RppH. Other members of the degradosome, including RNase Y, RNase J2, and RnpA, also cleave transcripts endonucleolytically. Secondary dsRNA structures are recognized and cleaved by the endoribonuclease RNase III. Resulting RNA pieces are then degraded in a 3′ 5′ fashion by the degradosome member PNPase and the degradosome‐independent RNase R. Fragments are then broken down in the 5′ 3′ direction by RNase J1. (c) The human exosome contains two structures: a ring structure composed of Rrp41, Rrp42, Mtr3, OIP2, Rrp46, and PM‐Scl75, and a cap structure containing Rrp4, Rrp40, and Csl4. These exosome core components associate with the 3′ 5′ exoribonucleases DIS3 and PM‐Scl100 in the nucleus, or the dual endo‐ and 3′ 5′ exo‐ribonuclease DIS3L in the cytoplasm. Degradation of mRNA is initiated by removal of the poly(A) tail by deadenylase activity, decapping of the 5′ end by the Dcp1/Dcp2 complex, or by the endoribonucleolytic activity of the exosome‐associated cytoplasmic DIS3L. The resulting mRNA is then vulnerable to 3′ 5′ degradation by the exosome‐associated PM‐Scl100, DIS3, or DIS3L, and 5′ 3′ decay by the exoribonucleases XRN2 (nucleus) or XRN1 (cytoplasm).

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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA in Disease and Development > RNA in Disease

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