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Abasic RNA: its formation and potential role in cellular stress response.

ABSTRACT: RNA is integral to gene expression as messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA) each play roles to transmit information from DNA into synthesis of functional proteins. During their lifespan, these nucleic acids may be chemically modified by alkylation, oxidation and the removal of bases, which alters their activity. Though much research has been devoted to the detection and repair of damaged DNA, RNA is viewed as a short-lived molecule that is quickly degraded upon damage. However, recent studies indicate that RNAs that become modified, particularly during stress, function as important signalling molecules. In this review, we focus on the effects of abasic RNAs and the modifications that lead to the loss of a base, as RNAs that are initially methylated or oxidized often become abasic. We describe how these chemical changes occur and cite recent work showing that in addition to being indicators of damage, abasic RNAs function as signals that mediate downstream cellular responses to stress.

SUBMITTER: Prashar T

PROVIDER: S-EPMC10281472 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Abasic RNA: its formation and potential role in cellular stress response.

Prashar Tanya T De La Selle Fernand F Hudak Katalin A KA

RNA biology 20230101 1

RNA is integral to gene expression as messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA) each play roles to transmit information from DNA into synthesis of functional proteins. During their lifespan, these nucleic acids may be chemically modified by alkylation, oxidation and the removal of bases, which alters their activity. Though much research has been devoted to the detection and repair of damaged DNA, RNA is viewed as a short-lived molecule that is quickly degraded upon damag ...[more]

PMID: 37322835

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Project description:While germline recessive loss-of-function mutations in SEC23B in humans cause a rare form of anaemia, heterozygous change-of-function mutations result in increased predisposition to cancer. SEC23B encodes SEC23 homologue B, a component of coat protein complex II (COPII), which canonically transports proteins from the endoplasmic reticulum (ER) to the Golgi. Despite the association of SEC23B with anaemia and cancer, the precise pathophysiology of these phenotypic outcomes remains unknown. Recently, we reported that mutant SEC23B has non-canonical COPII-independent function, particularly within the ER stress and ribosome biogenesis pathways, and that may contribute to the pathobiology of cancer predisposition. In this study, we hypothesized that wild-type SEC23B has a baseline function within such cellular stress response pathways, with the mutant protein reflecting exaggerated effects. Here, we show that the wild-type SEC23B protein localizes to the nucleus in addition to classical distribution at the ER/Golgi interface and identify multiple putative nuclear localization and export signals regulating nuclear-cytoplasmic transport. Unexpectedly, we show that, independently of COPII, wild-type SEC23B can also localize to cell nucleoli under proteasome inhibition conditions, with distinct distribution patterns compared to mutant cells. Unbiased proteomic analyses through mass spectrometry further revealed that wild-type SEC23B interacts with a subset of nuclear proteins, in addition to central proteins in the ER stress, protein ubiquitination, and EIF2 signalling pathways. We validate the genotype-specific differential SEC23B-UBA52 (ribosomal protein RPL40) interaction. Finally, utilizing patient-derived lymphoblastoid cell lines harbouring either wild-type or mutant SEC23B, we show that SEC23B levels increase in response to ER stress, further corroborating its role as a cellular stress response sensor and/or effector. Overall, these observations suggest that SEC23B, irrespective of mutation status, has unexplored roles in the cellular stress response pathway, with implications relevant to cancer and beyond that, CDAII and normal cell biology.

Dataset Information

Abasic RNA: its formation and potential role in cellular stress response.

Publications

Abasic RNA: its formation and potential role in cellular stress response.

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