The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis

Farg, Manal A.; Konopka, Anna; Soo, Kai Y.; Ito, Daisuke; Atkin, Julie D.

doi:10.1093/hmg/ddx170

Cited by 132 publications

(119 citation statements)

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“…Various molecules (i.e. FEN1, hnRNPK, NPM1, PABPC1, SFPQ and XRCC1) were already described as APE1-interacting partners in other studies from this 4,12 and other groups 24,29,30 , confirming the good quality of our analysis. The following proximity ligation assays were then successfully carried out to validate the identified APE1-interacting proteins within cells: i) SFPQ (splicing factor, proline-and glutamine-rich), DHX9 (DEAH-box helicase 9) and hnRNPK (heterogeneous nuclear ribonucleoprotein K) in HeLa cells ( Fig.…”

Section: Resultssupporting

confidence: 82%

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Ayyildiz

Antoniali

D’Ambrosio

et al. 2020

Sci Rep

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APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecting different subnetworks largely composed of proteins belonging to cancer-associated communities and/or involved in RNA-and DNA-metabolism. When we performed survival analysis in real cancer datasets, we observed that more than 80% of these APE1-PPI network elements is associated with bad prognosis. Our findings, which are hypothesis generating, strongly support the possibility to infer APE1-interactomic signatures associated with bad prognosis of different cancers; they will be of general interest for the future definition of novel predictive disease biomarkers. Future studies will be needed to assess the function of APE1 in the protein complexes we discovered. Data are available via ProteomeXchange with identifier PXD013368.Alteration of DNA repair mechanisms is an important hallmark of cancer cells, and plays a role both in the onset of an initial cancerous phenotype and in tumor progression. Tumor cells can develop drug resistance through repair mechanisms that counteract the DNA damage induced by chemotherapy or radiotherapy 1,2 . Thus, specific DNA repair inhibitors are often combined with DNA-damaging agents to improve therapy efficacy. Emerging evidences in tumor biology suggest that: i) protein-protein interactions (PPIs) specifically modulate both canonical and non-canonical roles of DNA repair enzymes; ii) RNA processing pathways participate in DNA-Damage Response (DDR); iii) defects in the above-mentioned regulatory mechanisms are associated with cancer genomic instability 3 . Very recent studies clearly show that many DNA repair proteins are associated with those involved in RNA metabolism, proving a role of their interactome network in undertaking non-canonical functions affecting gene expression in tumors. In addition, novel studies have shown that interaction of DDR components and miRNA biogenesis process is linked to cancer development 2 . In the context of these emerging lines, we already demonstrated the crucial role that enzymes belonging to the base excision DNA repair (BER) pathway play 4 . In particular, we showe...

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Section: Resultssupporting

confidence: 82%

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Ayyildiz

Antoniali

D’Ambrosio

et al. 2020

Sci Rep

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“…This is consistent with our previous work that did not show any inhibition of huntingtin nuclear localization in response to stress, but instead showed inhibition of relief of that response (42). In other neurological diseases, recent publications have noted trapped DNA repair complexes, and in particular, complexes that involve ATM kinase (43,44). Thus, future work will focus on the role of HMGB1 within huntingtin-ATM DNA repair complexes and the potential disruption of the N17/HMGB1 or IVS/HMGB1 interface to prevent mutant huntingtin nuclear entry.…”

Section: Hmgb1 Regulates the Huntingtin Nuclear Localization Signalmentioning

confidence: 97%

High-mobility group box 1 links sensing of reactive oxygen species by huntingtin to its nuclear entry

Son

Bowie

Maiuri

et al. 2019

Journal of Biological Chemistry

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Edited by Ursula JakobHuntington's disease (HD) is a neurodegenerative, age-onset disorder caused by a CAG DNA expansion in exon 1 of the HTT gene, resulting in a polyglutamine expansion in the huntingtin protein. Nuclear accumulation of mutant huntingtin is a hallmark of HD, resulting in elevated mutant huntingtin levels in cell nuclei. Huntingtin is normally retained at the endoplasmic reticulum via its N17 amphipathic ␣-helix domain but is released by oxidation of Met-8 during reactive oxygen species (ROS) stress. Huntingtin enters the nucleus via an importin ␤1and 2-dependent proline-tyrosine nuclear localization signal (PY-NLS), which has a unique intervening sequence in huntingtin. Here, we have identified the high-mobility group box 1 (HMGB1) protein as an interactor of the intervening sequence within the PY-NLS. Nuclear levels of HMGB1 positively correlated with varying levels of nuclear huntingtin in both HD and normal human fibroblasts. We also found that HMGB1 interacts with the huntingtin N17 region and that this interaction is enhanced by the presence of ROS and phosphorylation of critical serine residues in the N17 region. We conclude that HMGB1 is a huntingtin N17/PY-NLS ROS-dependent interactor, and this protein bridging is essential for relaying ROS sensing by huntingtin to its nuclear entry during ROS stress. ROS may therefore be a critical age-onset stress that triggers nuclear accumulation of mutant huntington in Huntington's disease.

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“…Accordingly, overexpression of TDP‐43 in Drosophila results in cell death due to many alterations, including DNA damage . Finally, overexpression of poly‐GR repeats in neurons is also able to induce DNA damage although the exact mechanism has not been clarified . Nonetheless, all this experimental evidence suggests that DNA damage contributes to FTLD together with the other mechanisms described above (Figure ).…”

Section: General Overview Of Ftld Pathological Mechanismsmentioning

confidence: 99%

Review: Molecular pathology of frontotemporal lobar degenerations

Borroni

Alberici

Buratti

2019

Neuropathology Appl Neurobio

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Frontotemporal lobar degeneration (FTLD) is a group of disorders that principally affect the frontal and temporal lobes of the brain. In many parts of the world, FTLD is rapidly becoming a serious health burden on society and, as a result, the molecular mechanisms that underlie its onset and development have been the target of intense research efforts in recent years. Nonetheless, despite crucial pathological and genetic discoveries in this area much is still uncertain about how the many genes associated with this disease cause the observed neurodegeneration. Moreover, it has not been easy to define the molecular mechanisms that account for the clinical and pathological heterogeneity of the various FTLD subtypes, characterized by aggregates of Tau, TAR‐DNA‐Binding Protein‐43 (TDP‐43), and less often Fused in Sarcoma (FUS) protein. In this review, we will examine some of the emerging discoveries in this field: from the recent importance of autoimmunity to the presence of substantial variations in the composition and localization of TDP‐43 and FUS brain aggregates in patients, and how they might affect the course of the disease. All together, these new results demonstrate how the observed clinical heterogeneity underlies considerable complexity at both the molecular and the disease pathway level. A better characterization of all this complexity will be essential for a more accurate stratification of patient cohorts for further studies and, eventually, for trials of therapy.

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The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis

Cited by 132 publications

References 50 publications

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

High-mobility group box 1 links sensing of reactive oxygen species by huntingtin to its nuclear entry

Review: Molecular pathology of frontotemporal lobar degenerations

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