SMN-deficient cells exhibit increased ribosomal DNA damage

Karyka, Evangelia; Ramirez, Nelly Berrueta; Webster, Christopher P; Marchi, Paolo; Godena, Vinay K.; Marrone, Lara; Bhargava, Anushka; Ray, Sujoy; Ning, Ke; Crane, Hannah; Hautbergue, Guillaume M.; El‐Khamisy, Sherif F.; Azzouz, Mimoun

doi:10.26508/lsa.202101145

Cited by 8 publications

(9 citation statements)

References 96 publications

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“…Our results show a newly discovered SMN function in nucleolar homeostasis and may directly impact the life and well-being of SMA patients 33 . In fact, in cells and motoneurons of SMA patients, exogenous and endogenous DNA damage might progressively and lastingly disrupt nucleolar structure and disturb ribosome biogenesis leading to perturbed protein translation 34 . This defect may contribute to the neurodegenerative phenotype of SMA motoneurons.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling between Nuclear Compartments

Musawi

Donnio

Magnani

et al. 2022

Preprint

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SMA is an autosomal recessive neuromuscular disease caused by mutations in the multifunctional protein SMN. Within the nucleus, SMN localizes to Cajal bodies (CBs), which have been shown to be associated with nucleoli, nuclear organelles dedicated to the first steps of ribosome biogenesis. The highly organized structure of the nucleolus can be dynamically altered by genotoxic agents. After a genotoxic stress, RNAP1, Fibrillarin (FBL) and nucleolar DNA are exported to the periphery of the nucleolus and once DNA repair is fully completed the organization of the nucleolus is restored. We found that SMN is required for the restoration of nucleolar structure after genotoxic stress. Unexpectedly, during DNA repair, SMN shuttles from the CBs to the nucleolus. This shuttling is important for the nucleolar homeostasis and relies on the presence of Coilin, FBL and the activity of PRMT1.

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Section: Discussionmentioning

confidence: 99%

Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling between Nuclear Compartments

Musawi

Donnio

Magnani

et al. 2022

Preprint

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“…In essence, the concept that SMN orchestrates a ribosome-centric platform for regulating mRNA translation offers a distinctive framework for expanding our understanding of the molecular mechanisms underlying the global translational defects observed in multiple models of SMA [ 2 , 10 , 17 , 19 , 60 ].…”

Section: Smn Functions As a Ribosome-associated Protein Acting As A H...mentioning

confidence: 99%

“…SMN plays fundamental roles in the biogenesis of ribonucleic particles [ 5–7 ], pre-mRNA splicing [ 8 ], and RNA metabolism at large [ 9 ]. In addition, SMN deficiency is likely linked to rDNA damage and impaired rRNA synthesis [ 10 ]. However, abnormalities in these functions observed in SMA cannot fully recapitulate the disease pathogenesis [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

The SMN-ribosome interplay: a new opportunity for Spinal Muscular Atrophy therapies

Sharma,

Paganin,

Lauria

et al. 2024

Biochemical Society Transactions

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The underlying cause of Spinal Muscular Atrophy (SMA) is in the reduction of survival motor neuron (SMN) protein levels due to mutations in the SMN1 gene. The specific effects of SMN protein loss and the resulting pathological alterations are not fully understood. Given the crucial roles of the SMN protein in snRNP biogenesis and its interactions with ribosomes and translation-related proteins and mRNAs, a decrease in SMN levels below a specific threshold in SMA is expected to affect translational control of gene expression. This review covers both direct and indirect SMN interactions across various translation-related cellular compartments and processes, spanning from ribosome biogenesis to local translation and beyond. Additionally, it aims to outline deficiencies and alterations in translation observed in SMA models and patients, while also discussing the implications of the relationship between SMN protein and the translation machinery within the context of current and future therapies.

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“…These findings include: the presence of P53-mediated DNA damage via dysregulation of P53 repressors Mdm2 and Mdm4 (Jangi et al, 2017 ; Simon et al, 2017 ; Van Alstyne et al, 2018 ), R-loop accumulation and R-loop-mediated DNA damage (Zhao et al, 2016 ; Jangi et al, 2017 ; Kannan et al, 2018 ), rescue of R-loop-mediated DNA damage (Kannan et al, 2020 ) and defects in the assembly of R-loop resolution complexes (RLRC) as a cause of nuclear/nucleolar R-loop accumulation and DNA damage in SMA (Kannan et al, 2022 ). A recent study shows that the knockdown of DDX21 may contribute to nucleolar R-loop accumulation and ribosomal DNA damage in SMN-deficient cells (Karyka et al, 2022 ). A timeline for the involvement of DNA damage and impaired DNA repair in SMA pathogenesis is shown in Figure 2 .…”

Section: Dna Damage In Smamentioning

confidence: 99%

“…A recent study identified nucleolar DEAD/H BOX RNA helicase 21 (DDX21) downregulation in SMA patient-derived IPSC motor neurons. DDX21 knockdown results in R-loop accumulation in the nucleolus, which may be a cause of ribosomal DNA damage in SMN-deficient cells (Karyka et al, 2022 ). Extensive mitochondrial pathology has also been reported in SMA, including mitochondrial DNA (mtDNA) damage, raising the question of whether mtDNA damage in SMA is R-loop mediated (Miller et al, 2016 ; James et al, 2021 ).…”

Section: R-loop-mediated Dna Damage In Smamentioning

confidence: 99%

R-loop Mediated DNA Damage and Impaired DNA Repair in Spinal Muscular Atrophy

Cuartas

Gangwani

2022

Front. Cell. Neurosci.

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Defects in DNA repair pathways are a major cause of DNA damage accumulation leading to genomic instability and neurodegeneration. Efficient DNA damage repair is critical to maintain genomicstability and support cell function and viability. DNA damage results in the activation of cell death pathways, causing neuronal death in an expanding spectrum of neurological disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and spinal muscular atrophy (SMA). SMA is a neurodegenerative disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motor neurons due to low levels of the SMN protein. The molecular mechanism of selective motor neuron degeneration in SMA was unclear for about 20 years. However, several studies have identified biochemical and molecular mechanisms that may contribute to the predominant degeneration of motor neurons in SMA, including the RhoA/ROCK, the c-Jun NH2-terminal kinase (JNK), and p53-mediated pathways, which are involved in mediating DNA damage-dependent cell death. Recent studies provided insight into selective degeneration of motor neurons, which might be caused by accumulation of R-loop-mediated DNA damage and impaired non-homologous end joining (NHEJ) DNA repair pathway leading to genomic instability. Here, we review the latest findings involving R-loop-mediated DNA damage and defects in neuron-specific DNA repair mechanisms in SMA and discuss these findings in the context of other neurodegenerative disorders linked to DNA damage.

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SMN-deficient cells exhibit increased ribosomal DNA damage

Cited by 8 publications

References 96 publications

Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling between Nuclear Compartments

Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling between Nuclear Compartments

The SMN-ribosome interplay: a new opportunity for Spinal Muscular Atrophy therapies

R-loop Mediated DNA Damage and Impaired DNA Repair in Spinal Muscular Atrophy

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