Screen identifies fasudil as a radioprotector on human fibroblasts

Yao, Yanling; Chen, Chen; Cai, Zuchao; Liu, Guochao; Ding, Chenxia; Lim, David; Dong, Chengliang; Feng, Zhihui

doi:10.1093/toxres/tfac042

Cited by 3 publications

(1 citation statement)

References 52 publications

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“…Inhibiting ROCK activity has been shown to prevent DNA damage and genome instability. [ 28 ] Importantly, the number of G1‐specific 53BP1 foci was restored to close to the baseline level when wild type (WT) or ANKLE1 −/− cells were treated with Y‐27632, in both untreated and ICRF‐193‐treated conditions (Figure 5c,d ). These results suggest that the action of ANKLE1 in midbody prevents excessive damage of chromosome bridges mediated by actomyosin contractility.…”

Section: Resultsmentioning

confidence: 97%

Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS‐STING Activation

et al. 2023

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Chromatin bridges connecting the two segregating daughter nuclei arise from chromosome fusion or unresolved interchromosomal linkage. Persistent chromatin bridges are trapped in the cleavage plane, triggering cytokinesis delay. The trapped bridges occasionally break during cytokinesis, inducing DNA damage and chromosomal rearrangements. Recently, Caenorhabditis elegans LEM‐3 and human TREX1 nucleases have been shown to process chromatin bridges. Here, it is shown that ANKLE1 endonuclease, the human ortholog of LEM‐3, accumulates at the bulge‐like structure of the midbody via its N‐terminal ankyrin repeats. Importantly, ANKLE1−/− knockout cells display an elevated level of G1‐specific 53BP1 nuclear bodies, prolonged activation of the DNA damage response, and replication stress. Increased DNA damage observed in ANKLE1−/− cells is rescued by inhibiting actin polymerization or reducing actomyosin contractility. ANKLE1 does not act in conjunction with structure‐selective endonucleases, GEN1 and MUS81 in resolving recombination intermediates. Instead, ANKLE1 acts on chromatin bridges by priming TREX1 nucleolytic activity and cleaving bridge DNA to prevent the formation of micronuclei and cytosolic dsDNA that activate the cGAS‐STING pathway. It is therefore proposed that ANKLE1 prevents DNA damage and autoimmunity by cleaving chromatin bridges to avoid catastrophic breakage mediated by actomyosin contractile forces.

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Section: Resultsmentioning

confidence: 97%

Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS‐STING Activation

et al. 2023

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Elucidating the impact of parthanatos-related microRNAs on the tumoral immune microenvironment and clinical outcome in low-grade gliomas

Zhu,

Wu,

Zheng

et al. 2024

Discov Onc

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Parthanatos, a cell death mechanism triggered by PARP-1 activation, is implicated in oncogenic processes, yet their role in low-grade gliomas (LGG) remains poorly understood. This research investigates Parthanatos-related miRNAs' prognostic and immunomodulatory potential, alongside their influence on therapeutic outcomes in LGGs. Comprehensive miRNA and mRNA profiles of LGG patients were extracted from TCGA and CGGA databases, integrating clinical parameters to identify Parthanatos-associated miRNAs. IHC data validated the expression levels of Parthanatos-related genes in glioma versus normal brain tissues. Protein–protein interaction networks and Spearman correlation analysis facilitated the identification of key miRNAs. Parthanatos-related miRNA indices (PMI) were screened using Lasso and assessed for their accuracy in predicting prognosis, comparing their associated potential molecular functions and heterogeneity of the immune microenvironment. Drug sensitivity was assessed between different groups and optimal therapeutic agents were predicted. Validate the expression levels of key miRNAs by qPCR. Ninety-one miRNAs significantly associated with Parthanatos were screened, through which a PMI prognosis model of nine miRNAs was constructed. The PMI score was able to independently predict the prognosis of patients with LGG, and the nomogram constructed based on the PMI provided a practical tool for clinical prediction of patient prognosis. The proportion of immune response was lower in patients in the high-risk group, and there were significant differences in drug sensitivity between different risk classes, while drugs such as Fasudil were identified as the most promising therapeutic agents for patients in the high-risk group. Our findings highlight the critical role of Parthanatos-associated miRNAs in the progression and treatment of LGG, offering novel insights into their prognostic value and therapeutic potential.

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Chromatin bridges: stochastic breakage or regulated resolution?

Jiang,

Chan

2024

Trends in Genetics

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Screen identifies fasudil as a radioprotector on human fibroblasts

Cited by 3 publications

References 52 publications

Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS‐STING Activation

Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS‐STING Activation

Elucidating the impact of parthanatos-related microRNAs on the tumoral immune microenvironment and clinical outcome in low-grade gliomas

Chromatin bridges: stochastic breakage or regulated resolution?

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