Telomerase-independent maintenance of telomere length in a vertebrate

Yu, Qinghao; Gates, Phillip B.; Rogers, Samuel; Mikičić, Ivan; Elewa, Ahmed; Salomon, Florian; Lachnit, Martina; Caldarelli, Antonio; Flores‐Rodriguez, Neftali; Cesare, Anthony J.; Simon, András; Yun, Maximina H.

doi:10.1101/2022.03.25.485759

Cited by 10 publications

(10 citation statements)

References 30 publications

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“…Recent developments in long-read sequencing methods (Wenger et al, 2019), assembly algorithms (Cheng et al, 2021; Nurk et al, 2020) and chromosome conformation capture methods (Hi-C) (Lieberman-Aiden et al, 2009) have enabled the generation of high-quality assemblies for species with giant genomes such as lungfish (c.40Gb, (Meyer et al, 2021; Wang et al, 2021)) and axolotl (c. 32Gb, (Nowoshilow et al, 2018; Schloissnig et al, 2021; Smith et al, 2019)). Comparing axolotl and newts among salamanders has identified key differences in terms of life cycle, regeneration repertoire, regeneration mechanisms, and genome composition (Joven et al, 2019; Yu et al, 2022). Hence it is important to also characterize the newts’ genomes in detail, to reveal the genetic basis of salamander-as well as species-specific mechanisms and innovations.…”

Section: Introductionmentioning

confidence: 99%

Sequencing and chromosome-scale assembly of the giantPleurodeles waltlgenome

Brown

Elewa

Iarovenko

et al. 2022

Preprint

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The Iberian ribbed newt (Pleurodeles waltl) constitutes a central model for probing the basis of regeneration. Here, we present the sequencing and chromosome-scale assembly of the 20.3Gb P. waltl genome, which exhibits the highest level of contiguity and completeness among giant genomes. We uncover that DNA transposable elements are the major contributors to its expansion, with hAT transposons comprising a large portion of repeats. Several hATs are actively transcribed and differentially expressed during adult P. waltl limb regeneration, along with domesticated hAT transposons of the ZBED transcription factor family. Despite its size, syntenic relationships are conserved across the genome. As an example we show the high degree of conservation of the regeneration-associated Tig1 locus with several neighbouring genes. Together, the P. waltl genome provides a fundamental resource for the study of regenerative, developmental and evolutionary principles.

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Section: Introductionmentioning

confidence: 99%

Sequencing and chromosome-scale assembly of the giantPleurodeles waltlgenome

Brown

Elewa

Iarovenko

et al. 2022

Preprint

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“…Structure of PIP-199 ( 1 ) and selected analogues reported in diverse medicinal chemistry literature ( 2 – 8 ). ,,− …”

Section: Introductionmentioning

confidence: 99%

Mannich Base PIP-199 Is a Chemically Unstable Pan-Assay Interference Compound

Sudhakar

Alcock

et al. 2023

J. Med. Chem.

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Mannich base PIP-199 is the only reported smallmolecule inhibitor of the Fanconi anemia complementation group M-RecQ-mediated genome instability protein (FANCM-RMI), a protein−protein interaction that governs genome instability in the genetic disorders Fanconi anemia and Bloom's syndrome. PIP-199 and analogues with the same indole-derived Mannich base scaffold have been used as tool compounds in diverse biological studies. We report the first published synthesis of PIP-199 and its analogues, demonstrating that PIP-199 immediately decomposes in common aqueous buffers and some organic solvents. Neither PIP-199 nor its more hydrolytically stable analogues show any observable activity in binding and competitive biophysical assays for FANCM-RMI. We conclude that PIP-199 is not an effective tool compound for biological studies and that apparent cellular activity likely arises from the nonspecific toxicity of breakdown products. More generally, apparent inhibitors that share this Mannich scaffold potentially represent a new family of pan-assay interference compounds (PAINS) that should be thoroughly assessed for aqueous stability prior to use in biological studies.

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“…Structure of PIP-199 (1) and selected analogues reported in diverse medicinal chemistry literature (2)(3)(4)(5)(6)(7)(8). [10][11][16][17][18][19][20][21] In this light, we report the first published literature synthesis of PIP-199 and unequivocally show that it is an unstable molecule when dissolved in common aqueous buffers as well as some organic solvents, raising significant questions about the interpretation of data obtained using this compound and its close analogues in biological studies.…”

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confidence: 95%

“…10,[12][13][14][15] PIP-199 was identified in an academic high-throughput screening campaign against FANCM-RMI and reported to bind the RMI1/RMI2 core complex in various orthogonal biophysical assays. 8 Since its report, commercially supplied PIP-199 (Figure 1) has been used in the literature as a tool compound for interrogating ALT in human cancer osteosarcoma models, 10 in vertebrate ALT models, 16 and to interrogate the prevalence and role of G-quadruplexes in the ALT mechanism. 11 Concerningly, PIP-199 and analogues (2)(3)(4)(5)(6) were also identified under different compound names in an earlier screening campaign against quorum sensing in bacteria, showing potent non-competitive inhibition of N-acyl-homoserine lactone synthase in Burkholderia mallei.…”

mentioning

confidence: 99%

Mannich base PIP-199 is a chemically unstable pan-assay interference compound

Sudhakar

Alcock

et al. 2023

Preprint

View full text Add to dashboard Cite

PIP-199 is the only reported small molecule inhibitor of FANCM-RMI, a key protein-protein interaction that governs genome instability in the genetic disorders Fanconi Anemia and Bloom’s Syndrome. PIP-199 and close analogues that share the same indole-derived Mannich base core scaffold have been used as commercially available tool compounds for studying a wide range of therapeutically relevant biological pathways and targets, including the Alternative Lengthening of Telomeres (ALT), G-quadruplexes, pro-apoptotic proteins, and quorum sensing. Herein, we report the first published synthesis of PIP-199 and related analogues, demonstrating that the parent compound immediately decomposes in common aqueous buffers and some organic solvents. We characterize the breakdown products and show that PIP-199 and its more hydrolytically stable analogues show no observable activity in binding and competitive biophysical assays for FANCM-RMI. We conclude that PIP-199 is not an effective tool compound for biological studies, and that apparent activity in cellular studies likely arises from non-specific toxicity of mixed breakdown products. More generally, apparent inhibitors that share this indole-derived Mannich scaffold potentially represent a new family of pan-assay interference compounds (PAINS) that should be thoroughly assessed for aqueous stability prior to use in biological studies.

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Telomerase-independent maintenance of telomere length in a vertebrate

Cited by 10 publications

References 30 publications

Sequencing and chromosome-scale assembly of the giantPleurodeles waltlgenome

Sequencing and chromosome-scale assembly of the giantPleurodeles waltlgenome

Mannich Base PIP-199 Is a Chemically Unstable Pan-Assay Interference Compound

Mannich base PIP-199 is a chemically unstable pan-assay interference compound

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