Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts DOI Creative Commons
Eka Putra Gusti Ngurah Putu, Laurent Cattiaux, Thomas Lavergne

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 51(20), С. 10846 - 10866

Опубликована: Окт. 18, 2023

Abstract Apurinic/apyrimidinic (AP) sites, 5-formyluracil (fU) and 5-formylcytosine (fC) are abundant DNA modifications that share aldehyde-type reactivity. Here, we demonstrate polyamines featuring at least one secondary 1,2-diamine fragment in combination with aromatic units form covalent adducts upon reaction AP sites (with concomitant cleavage of the strand), fU and, to a lesser extent, fC residues. Using small-molecule mimics site fU, show 1,2-diamines leads formation unprecedented 3′-tetrahydrofuro[2,3,4-ef]-1,4-diazepane (‘ribodiazepane’) scaffold, whereas produces cationic 2,3-dihydro-1,4-diazepinium via uracil ring opening. The reactivity towards versus can be tuned by modulating their chemical structure pH medium, enabling up 20-fold chemoselectivity for respect fC. This is efficient near-physiological conditions low-micromolar concentration tolerant presence large excess unmodified DNA. Remarkably, 3′-ribodiazepane chemically stable resistant action apurinic/apyrimidinic endonuclease 1 (APE1) tyrosyl-DNA phosphoesterase (TDP1), two repair enzymes known cleanse variety 3′ end-blocking lesions.

Язык: Английский

DNA Repair Pathways in the Mitochondria DOI
Dillon E. King, William C. Copeland

DNA repair, Год журнала: 2025, Номер 146, С. 103814 - 103814

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

2
35 Years of TFAM Research: Old Protein, New Puzzles DOI Creative Commons

Natalya Kozhukhar,

Mikhail Alexeyev

Biology, Год журнала: 2023, Номер 12(6), С. 823 - 823

Опубликована: Июнь 6, 2023

Transcription Factor A Mitochondrial (TFAM), through its contributions to mtDNA maintenance and expression, is essential for cellular bioenergetics and, therefore, the very survival of cells. Thirty-five years research on TFAM structure function generated a considerable body experimental evidence, some which remains be fully reconciled. Recent advancements allowed an unprecedented glimpse into complexed with promoter DNA within open complexes. These novel insights, however, raise new questions about this remarkable protein. In our review, we compile available literature provide critical analysis data.

Язык: Английский

Процитировано

13
Mitochondrial transcription factor A (TFAM) has 5′-deoxyribose phosphate lyase activity in vitro DOI Creative Commons
W. R. Zhao,

Adil S. Hussen,

Bret Freudenthal

и другие.

DNA repair, Год журнала: 2024, Номер 137, С. 103666 - 103666

Опубликована: Март 8, 2024

Язык: Английский

Процитировано

4
DNA sequence and lesion-dependent mitochondrial transcription factor A (TFAM)-DNA-binding modulates DNA repair activities and products DOI Creative Commons
Kathleen M. Urrutia,

Yu Hsuan Chen,

Jin Tang

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 28, 2024

Abstract Mitochondrial DNA (mtDNA) is indispensable for mitochondrial function and maintained by repair, turnover, dynamics mitophagy, along with the inherent redundancy of mtDNA. Base excision repair (BER) a major mechanism in mammalian mitochondria. BER enzymes are implicated mtDNA-mediated immune response inflammation. mtDNA organized into nucleoids transcription factor A (TFAM). The regulation activities TFAM-DNA interactions remains understudied. Here, we demonstrate modulation TFAM concentrations, sequences modifications. Unlike previously reported inhibitory effects, observed that human uracil-DNA glycosylase 1 (UNG1) AP endonuclease I (APE1) have optimal at specific TFAM/DNA molar ratios. High ratios inhibited other enzymes, OGG1 AAG. In addition, reduces accumulation certain intermediates. Molecular simulations DNA-binding experiments presence 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) sequence motifs enhances binding, partially explaining inhibition activity. Bioinformatic analysis published 8-oxodG, dU, TFAM-footprint maps reveals correlation between 8-oxodG locations Collectively, these results highlight complex sequence, lesions enzymes.

Язык: Английский

Процитировано

4
Chemical Switching: A Concept Inspired by Strategies from Biocatalysis and Organocatalysis DOI Creative Commons
Torkild Visnes, Kaixin Zhou, Aurino M. Kemas

и другие.

ChemBioChem, Год журнала: 2025, Номер unknown

Опубликована: Май 26, 2025

In this perspective the character of aldehyde functional groups is outlined as central intermediates in DNA repair. As highly reactive entities, aldehydes exist limited quantities and contextualized scenarios only are commonly masked a Schiff base. Recent advances reveal that principles organic chemistry can modulate enzymatic cleavage bases, process termed chemical switching. This approach not enhances production canonical repair products, bolstering cellular function, but also generates novel reaction intermediates, potentially rewiring pathways. However, such could increase complexity toxicity influencing therapeutic outcomes. To shape classes therapeutics, an exploitation these fine‐tuned requires expertise enzymologists scientists skilled bio‐ organocatalysis. Here, current state art chemically switching function cells with focus on repair, highlighting challenges new type protein modulation discussing possible solutions. paints picture concept emerging playing field exciting translational prospects.

Язык: Английский

Процитировано

0
Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts DOI Creative Commons
Eka Putra Gusti Ngurah Putu, Laurent Cattiaux, Thomas Lavergne

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 51(20), С. 10846 - 10866

Опубликована: Окт. 18, 2023

Abstract Apurinic/apyrimidinic (AP) sites, 5-formyluracil (fU) and 5-formylcytosine (fC) are abundant DNA modifications that share aldehyde-type reactivity. Here, we demonstrate polyamines featuring at least one secondary 1,2-diamine fragment in combination with aromatic units form covalent adducts upon reaction AP sites (with concomitant cleavage of the strand), fU and, to a lesser extent, fC residues. Using small-molecule mimics site fU, show 1,2-diamines leads formation unprecedented 3′-tetrahydrofuro[2,3,4-ef]-1,4-diazepane (‘ribodiazepane’) scaffold, whereas produces cationic 2,3-dihydro-1,4-diazepinium via uracil ring opening. The reactivity towards versus can be tuned by modulating their chemical structure pH medium, enabling up 20-fold chemoselectivity for respect fC. This is efficient near-physiological conditions low-micromolar concentration tolerant presence large excess unmodified DNA. Remarkably, 3′-ribodiazepane chemically stable resistant action apurinic/apyrimidinic endonuclease 1 (APE1) tyrosyl-DNA phosphoesterase (TDP1), two repair enzymes known cleanse variety 3′ end-blocking lesions.

Язык: Английский

Процитировано

4