Functions of FUS/TLS From DNA Repair to Stress Response: Implications for ALS

Sama, Reddy Ranjith Kumar; Ward, Catherine L.; Bosco, Daryl A.

doi:10.1177/1759091414544472

Cited by 106 publications

(121 citation statements)

References 145 publications

(278 reference statements)

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“…However, these results do not rule out the possibility that unrepaired transcription-associated DNA damage contributes to motor neuron death in ALS. Based on work described here and that of others (5,6), it is reasonable to propose a model of ALS pathogenesis in which various ALS proteins, such as FUS and TDP43, prevent or repair various forms of transcription-associated DNA damage e.g., R loop-associated damage. Perhaps, through the stable formation of hydrogel or fibrous states (32,33), mutated ALS-related proteins with low complexity (LC) domains like FUS, TDP43, EWSR1, or TAF15 lose an important nuclear function and thereby fail to respond to transcription-associated DNA damage.…”

Section: Discussionmentioning

confidence: 96%

“…Animal models and cell-based assays have illuminated certain functions of FUS and TDP43 in both cycling and terminally differentiated cells (3)(4)(5). Work on TDP43 has suggested roles for it in transcription regulation, mRNA splicing, mRNA transport, and stress granule formation among other functions (4).…”

Section: Dna Damage Response | Als | Transcription | R Loopmentioning

confidence: 99%

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Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

108

119

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loopassociated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.A myotrophic lateral sclerosis (ALS) is a disease of both upper and lower motor neuron dysfunction that leads to progressive paralysis and eventually death due to respiratory failure. No single model of ALS disease pathogenesis has been revealed; however, multiple disease-associated genes are known (1). The variation in function of these genes suggests that there may be multiple ALS molecular subtypes. That said, the familial ALS gene product list is also enriched in protein groups with related functions.Mutations in multiple RNA processing genes, including FUS (FUS RNA-binding protein), TDP43 (TAR DNA-binding protein), SETX (senataxin), TAF15 (TATA box-binding protein-associated factor 15), EWSR1 (EWS RNA-binding protein 1), HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), and HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), among others, give rise to familial ALS (fALS) (1). FUS and TDP43 are currently the best studied, given that mutations in these genes lead to classic histologic findings in ALS neural tissue and that similar histologic findings can be found in neural tissue of sporadic ALS cases (2). At autopsy, cytoplasmic TDP43 inclusions are found in ALS motor neurons from patients with (i) TDP43 mutations and (ii) sporadic ALS (i.e., patients with no FUS, TDP43, or other known pathogenic mutation) (2). They are also present in neurons in various parts of the brains of patients with either sporadic or familial versions of the ALS-related disorder, fronto-temporal lobar dementia (FTLD) (2). At autopsy, FUS inclusions were detected in the cytoplasm of motor neurons of FUS mutation-bearing fALS patients and in the cytoplasm of neurons in various regions of the brain in some FTLD patients (2).FUS and TDP43 exhibit a wide range of functions, most of which involv...

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Section: Discussionmentioning

confidence: 96%

Section: Dna Damage Response | Als | Transcription | R Loopmentioning

confidence: 99%

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

108

119

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“…[50][51][52] Aberrations in FUS also represent one of the primary hallmarks of ALS cellular pathology, identified in 4-6% of FALS and 0.7-1.8% SALS cases. 53 These mutations result in a hyperosmolar cytosolic environment where localization of mutant aggregates can occur.…”

Section: Fused In Sarcoma (Fus)mentioning

confidence: 99%

“…53 These mutations result in a hyperosmolar cytosolic environment where localization of mutant aggregates can occur. 51 These aggregates form stress granules similar to and occasionally co-expressed with TDP-43 and SOD1, where local RNA molecules play an as yet undetermined role in granule stability. 54,55 Furthermore, FUS irregularities disrupt correct localization of RNA binding proteins, disrupting nuclear cellular events.…”

Section: Fused In Sarcoma (Fus)mentioning

confidence: 99%

“…56 One current theory posits the disruption in FUS localization prevents correct DNA damage repair, resulting in accumulation of injurious insults to motor neurons and culminating in stereotyped ALS symptomology. 51 FUS mutants also express deficiencies in autoregulation, leading to an increased vulnerability to cellular stress and degeneration manifesting as axon withdrawal, synapse dysfunction, and muscular denervation. 52 Animal models in Drosophila have demonstrated that mutations in FUS analog Cabeza (Caz) causes in vivo toxicity by disrupting neuromuscular junctions and inducing apoptosis in motor neurons.…”

Section: Fused In Sarcoma (Fus)mentioning

confidence: 99%

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Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

Sanford¹

2015

MJM

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Fused in sarcoma undergoes cold denaturation: Implications for phase separation

et al. 2022

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The mediation of liquid-liquid phase separation (LLPS) for fused in sarcoma (FUS) protein is generally attributed to the low-complexity, disordered domains and is enhanced at low temperature. The role of FUS folded domains on the LLPS process remains relatively unknown since most studies are mainly based on fragmented FUS domains. Here, we investigate the effect of metabolites on full-length (FL) FUS LLPS using turbidity assays and differential interference contrast (DIC) microscopy, and explore the behavior of the folded domains by nuclear magnetic resonance (NMR) spectroscopy. FL FUS LLPS is maximal at low concentrations of glucose and glutamate, moderate concentrations of NaCl, Zn 2+ , and Ca 2+ and at the isoelectric pH. The FUS RNA recognition motif (RRM) and zinc-finger (ZnF) domains are found to undergo cold denaturation above 0 C at a temperature that is determined by the conformational stability of the ZnF domain. Cold unfolding exposes buried nonpolar residues that can participate in LLPS-promoting hydrophobic interactions. Therefore, these findings constitute the first evidence that FUS globular domains may have an active role in LLPS under cold stress conditions and in the assembly of stress granules, providing further insight into the environmental regulation of LLPS.

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Functions of FUS/TLS From DNA Repair to Stress Response: Implications for ALS

Cited by 106 publications

References 145 publications

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

Fused in sarcoma undergoes cold denaturation: Implications for phase separation

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