C9orf72 functions in the nucleus to regulate DNA damage repair

He, Li-Ying; Liang, Jiaqi; Chen, Chao-Nan; Chen, Ji‐Jun; Shen, Yuemao; Sun, Shuhui; Li, Lei

doi:10.1038/s41418-022-01074-0

Cited by 20 publications

(8 citation statements)

References 77 publications

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“…Surprisingly, we also showed that DJ-1 deficiency impairs the initial formation of γH2AX foci after DNA damage. It has been well reported that the formation of γH2AX foci is a marker of early DDR, and that γH2AX can amplify DDR signaling by recruiting DNA repair proteins [51,52]. Thus, our findings suggest that DJ-1 may play a role in the early stage of DDR.…”

Section: Discussionsupporting

confidence: 59%

Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity

Wang

Liu

et al. 2023

IJMS

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DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson’s disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations.

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Section: Discussionsupporting

confidence: 59%

Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity

Wang

Liu

et al. 2023

IJMS

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“…Other vital cellular mechanisms are co-regulated by C9orf72 protein and PRMT activity. One recent publication found that C9orf72 is involved in recruiting DNA repair enzymes to double-stranded breaks when localized to the nucleus, and that repair of double-stranded DNA breaks following polyGR overexpression is reduced in C9orf72-deficient cells ( He et al, 2022 ). PRMTs have a vast set of roles in the DNA damage response that vary by PRMT enzyme and arginine methylation type ( Lorton and Shechter, 2019 ; Urulangodi and Mohanty, 2020 ; Brobbey et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Dane

Gill

Vieira

et al. 2023

Front. Cell. Neurosci.

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IntroductionIntronic repeat expansions in the C9orf72 gene are the most frequent known single genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeat expansions are believed to result in both loss-of-function and toxic gain-of-function. Gain-of-function results in the production of toxic arginine-rich dipeptide repeat proteins (DPRs), namely polyGR and polyPR. Small-molecule inhibition of Type I protein arginine methyltransferases (PRMTs) has been shown to protect against toxicity resulting from polyGR and polyPR challenge in NSC-34 cells and primary mouse-derived spinal neurons, but the effect in human motor neurons (MNs) has not yet been explored.MethodsTo study this, we generated a panel of C9orf72 homozygous and hemizygous knockout iPSCs to examine the contribution of C9orf72 loss-of-function toward disease pathogenesis. We differentiated these iPSCs into spinal motor neurons (sMNs).ResultsWe found that reduced levels of C9orf72 exacerbate polyGR15 toxicity in a dose-dependent manner. Type I PRMT inhibition was able to partially rescue polyGR15 toxicity in both wild-type and C9orf72-expanded sMNs.DiscussionThis study explores the interplay of loss-of-function and gain-of-function toxicity in C9orf72 ALS. It also implicates type I PRMT inhibitors as a possible modulator of polyGR toxicity.

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“…Immunoblotting was performed as previously 43,52 . Cells were lysed in common RIPA buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 1% Triton X-100, 10% glycerol and protease inhibitor Cocktail (APExBIO)) and the brain tissues were lysed in RIPA Lysis Buffer (Beyotime) (50 mM Tris pH 7.4, 150 mM NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS).…”

Section: Immunoblotting and Immunoprecipitationmentioning

confidence: 99%

“…Immunostaining was performed as described previously 52 . The cultured neurons were xed with 4% paraformaldehyde (PFA) for 20 min at room temperature, blocked by the immunostaining buffer (1% BSA, 0.5% Triton X-100 in PBS) for 15 min at room temperature, and subsequently incubated with primary antibodies diluted in the immunostaining buffer overnight at 4°C.…”

Section: Immunostainingmentioning

confidence: 99%

Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation

Li,

Sun,

et al. 2024

Preprint

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Posttranslational modifications (PTMs) of tubulin, termed as the "tubulin code", play important roles in regulating microtubule functions within subcellular compartments for specialized cellular activities. While numerous tubulin PTMs have been identified, a comprehensive understanding of the complete repertoire is still underway. In this study, we report that α-tubulin lactylation catalyzed by HDAC6 by using lactate to increase microtubule dynamics in neurons. We identified lactylation on lysine 40 of α-tubulin in the soluble tubulin dimers. Notably, lactylated α-tubulin enhanced microtubule dynamics and facilitated neurite outgrowth and branching in cultured hippocampal neurons. Moreover, we discovered a novel function of HDAC6, acting as the primary “writer” for α-tubulin lactylation. HDAC6-catalyzed lactylation was a reversible process, dependent on lactate concentrations. Intracellular lactate concentration triggered HDAC6 to lactylate α-tubulin, a process dependent on its deacetylase activity. Additionally, the catalytic activity for lactylation was conserved in HDAC family proteins. Our study reveals the primary role of HDAC6 in regulating α-tubulin lactylation, establishing a link between cell metabolism and cytoskeleton functions.

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C9orf72 functions in the nucleus to regulate DNA damage repair

Cited by 20 publications

References 77 publications

Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity

Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation

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