PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

Rulten, Stuart L.; Rotheray, Amy; Green, Ryan L.; Grundy, Gabrielle J.; Moore, Duncan A. Q.; Gómez-Herreros, Fernando; Hafezparast, Majid; Caldecott, Keith W.

doi:10.1093/nar/gkt835

Cited by 164 publications

(160 citation statements)

References 46 publications

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“…Based on the results described here and the work of others, there is already support for this view of ALS pathogenesis, especially with respect to FUS-related cases. Our results fit with earlier observations showing that FUS localizes to sites of UV-laser induced DSBs and supporting a role for FUS in DNA repair (6,7,19).…”

Section: Discussionsupporting

confidence: 92%

“…The finding that FUS participates in the prevention or repair of transcription-associated DNA damage is consistent with the prior finding that FUS localizes to DSBs induced by a UV laser (6,7,19). The latter observation suggests two functional possibilities: (i) that FUS participates in the repair of DSBs, per se, and (ii) that it localizes to breaks located near sites of transcription-associated DNA damage.…”

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription supporting

confidence: 89%

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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: Discussionsupporting

confidence: 92%

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription supporting

confidence: 89%

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

View full text Add to dashboard Cite

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“…FUS has also previously been implicated in DNA repair (Rulten et al, 2014;Wang et al, 2013). Indeed, we found that FUS accumulated at DNA lesions within a second of laser-mediated irradiation (Figures 1D, S1C, and S1D; Movie S1).…”

Section: Resultssupporting

confidence: 58%

“…The Prion-like Protein FUS Assembles into Various Dynamic Compartments In Vivo Previous reports have implicated FUS in the formation of stressinducible compartments, such as DNA damage sites and stress granules Mastrocola et al, 2013;Rulten et al, 2014;Wang et al, 2013). These studies often used transient transfection protocols and overexpression plasmids to study the subcellular localization of FUS.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, we found that PAR polymerase 1 (PARP1) arrives within seconds of DNA damage, and FUS was detectable immediately after arrival of PARP1 (Figure 4A). To investigate whether PAR is required for FUS accumulation, we interfered with PAR formation by adding an inhibitor of PARP1/2 to cells shortly before laser-mediated irradiation (Rulten et al, 2014). Indeed, inhibition of PARP1/2 prevented the recruitment of FUS ( Figures 4B and 4C).…”

Section: Multivalent Par Chains Nucleate Fus Droplets In Vivo and In mentioning

confidence: 99%

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A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation

Patel

Lee

Jawerth

et al. 2015

Cell

2,520

147

3,091

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Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases.

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RNase L facilitates the repair of DNA double‐strand breaks through the nonhomologous end‐joining pathway

Zhong¹,

Pan

Zhu³

et al. 2019

FEBS Letters

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RNA molecules have been found to play important roles in DNA double‐strand break (DSB) repair, but the exact underlying mechanism remains unclear. Here, we aimed to clarify the function of RNase L, an important ribonuclease in the immune system of vertebrates, in DSB repair. Knockdown of RNase L reduces cell survival after induction of DSBs by ionizing radiation or camptothecin and causes a significant decrease in DSB repair, as evidenced by an increase in the extent of phosphorylation of histone H2AX on Ser139 (γH2AX) and γH2AX nuclear foci formation. Thus, our findings indicate that RNase L interacts with the core factors involved in DNA end joining, such as XRCC4 and Lig4, and facilitates DSB repair through the nonhomologous end‐joining pathway.

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PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

Cited by 164 publications

References 46 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

A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation

RNase L facilitates the repair of DNA double‐strand breaks through the nonhomologous end‐joining pathway

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