Origin and significance of the human DNase repertoire

Mori, Giulia; Delfino, Danila; Pibiri, Paola; Rivetti, Claudio; Percudani, Riccardo

doi:10.1038/s41598-022-14133-w

Cited by 7 publications

(9 citation statements)

References 69 publications

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Section: Resultsmentioning

confidence: 99%

Cysteine Enrichment Mediates Co-Option of Uricase in Reptilian Skin and Transition to Uricotelism

Mori,

Liuzzi,

Ronda

et al. 2023

Molecular Biology and Evolution

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Uric acid is the main means of nitrogen excretion in uricotelic vertebrates (birds and reptiles) and the end product of purine catabolism in humans and a few other mammals. While uricase is inactivated in mammals unable to degrade urate, the presence of orthologous genes without inactivating mutations in avian and reptilian genomes is unexplained. Here we show that the Gallus gallus gene we name cysteine-rich urate oxidase (CRUOX) encodes a functional protein representing a unique case of cysteine enrichment in the evolution of vertebrate orthologous genes. CRUOX retains the ability to catalyze urate oxidation to hydrogen peroxide and 5-hydroxyisourate (HIU), albeit with a 100-fold reduced efficiency. However, differently from all uricases hitherto characterized, it can also facilitate urate regeneration from HIU, a catalytic property that we propose depends on its enrichment in cysteine residues. X-ray structural analysis highlights differences in the active site compared to known orthologs and suggests a mechanism for cysteine-mediated self-aggregation under H2O2-oxidative conditions. Cysteine enrichment was concurrent with the transition to uricotelism and a shift in gene expression from the liver to the skin where CRUOX is co-expressed with β-keratins. Therefore, the loss of urate degradation in amniotes has followed opposite evolutionary trajectories: while uricase has been eliminated by pseudogenization in some mammals, it has been repurposed as a redox-sensitive enzyme in the reptilian skin.

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Section: Resultsmentioning

confidence: 99%

Cysteine Enrichment Mediates Co-Option of Uricase in Reptilian Skin and Transition to Uricotelism

Mori,

Liuzzi,

Ronda

et al. 2023

Molecular Biology and Evolution

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“…DNases are essential enzymes in maintaining human health [99]. DNases degrade the phosphodiester bonds in DNA molecules.…”

Section: Dnasesmentioning

confidence: 99%

“…DNases have evolved in human along with the phagocytosis to aid in bacterial DNA degradation according to the most prominent hypothesis [100]. Also, DNases have evolved as a protection machinery that degrades self-DNA intra-or extracellularly under physiological or pathological condition, preventing its harmful accumulation [99]. There are two families of DNases that differ in biochemical characteristics.…”

Section: Dnasesmentioning

confidence: 99%

Nuclease Activity as a Biomarker in Cancer Detection

Balian

2023

Linköping Studies in Science and Technology. Dissertations

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Nucleases are a group of enzymes that cleave the phosphodiester bonds in nucleic acids. As such, nucleases act as biological scissors that exhibit a plethora of fundamental roles, in prokaryotes and eukaryotes, dependent or non-dependent on their catalytic capability. Thus, differential status of nucleases between healthy and disease conditions might not be surprising, and can be deployed in disease detection. Specifically, there is growing body of research demonstrating the potential of nucleases as diagnostic biomarkers in several types of cancer. Biomarkers for early diagnosis are an immense need in the diagnostic landscape of cancer. In this sense, nucleases are promising biomolecules, and they possess a unique feature of catalytic activity that could be deployed for diagnosis and future therapeutic strategies. In this thesis we aim to demonstrate the use of nucleases as biomarkers associated to cancer, and the capability of oligonucleotide substrates for targeting a specific nuclease.xiii I am deeply grateful to my lovely family, my supporter in all my endeavors. Thank you, Mom, Dad and Alexan for all your love, encouragement and believing in me. Mom, I deeply appreciate your unlimited love and care for me and Ella, and I am beyond thankful for always being there when I needed time to focus on my work and writing.I want to give a big thanks to my husband Rami for encouraging me to take this path, and for his love and support all the way. I am lucky and beyond grateful for having you by my side. Big thanks also to my daughter Ella who opened my heart to new horizons of love. Thank you for being my sweetest supporter ever, especially when you say "Jag vill bli som du mamma". And I want to say what I always tell you: Jag älskar dig så mycket. Norrköping, December 2022 Alien Balian xv Papers Included in the Thesis I. Nucleases as Molecular Targets for Cancer Diagnosis Balian A., Hernandez FJ. Biomark Res., (2021), 9(1):86.Author's contribution: AB has conducted literature search, written all the sections, made the initial design of the figures and responded to the reviewers' comments to edit the paper.

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“…The Uox-Dnase2b locus with a head-to-head arrangement is present in conserved synteny in metazoans (Mori et al 2022). Among reptiles, chelonians (tortoises and turtles) have a duplicate Uox, which we call Uox2, and which lies tail-to-tail with Dnase2b (S14A To evaluate the effect of these substitutions on uricase activity, we mutated the tyrosine in the active site of GgUox to either histidine (Y230H), as observed in chelonian Uox, or valine (Y230V), as in a canonical Uox sequence.…”

Section: Uricase Gene Duplication In Chelonian Reptilesmentioning

confidence: 99%

Cysteine enrichment mediates co-option of uricase in reptilian skin and transition to uricotelism

Mori,

Liuzzi,

Ronda

et al. 2023

Preprint

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Uric acid is the main means of nitrogen excretion in uricotelic vertebrates (birds and reptiles) and the end product of purine catabolism in humans and a few other mammals. While uricase is inactivated in mammals unable to degrade urate, the presence of orthologous genes without inactivating mutations in avian and reptilian genomes is unexplained. Here we show that the Gallus gallus gene we name cysteine-rich urate oxidase (CRUOX) encodes a functional protein representing a unique case of cysteine enrichment in the evolution of vertebrate orthologous genes. CRUOX retains the ability to catalyze urate oxidation to hydrogen peroxide and 5-hydroxyisourate (HIU), albeit with a 100-fold reduced efficiency. However, differently from all uricases hitherto characterized, it can also facilitate urate regeneration from HIU, a catalytic property which we propose depends on its enrichment in cysteine residues. X-ray structural analysis highlights differences in the active site compared to known orthologs and suggests a mechanism for cysteine-mediated self-aggregation under H2O2-oxidative conditions. Cysteine enrichment was concurrent with transition to uricotelism and a shift in gene expression from the liver to the skin where CRUOX is co-expressed with β-keratins. Therefore, the loss of urate degradation in amniotes has followed opposite evolutionary trajectories: while uricase has been eliminated by pseudogenization in some mammals, it has been repurposed as a redox-sensitive enzyme in the reptilian skin.

show abstract

Origin and significance of the human DNase repertoire

Cited by 7 publications

References 69 publications

Cysteine Enrichment Mediates Co-Option of Uricase in Reptilian Skin and Transition to Uricotelism

Cysteine Enrichment Mediates Co-Option of Uricase in Reptilian Skin and Transition to Uricotelism

Nuclease Activity as a Biomarker in Cancer Detection

Cysteine enrichment mediates co-option of uricase in reptilian skin and transition to uricotelism

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