Dimeric structures of DNA ATTTC repeats promoted by divalent cations

Trajkovski, Marko (author), Pastore, Annalisa (author), Plavec, Janez (author)

Structural studies of repetitive DNA sequences may provide insights why and how certain repeat instabilities in their number and nucleotide sequence are managed or even required for normal cell physiology, while genomic variability associated with repeat expansions may also be disease-causing. The pentanucleotide ATTTC repeats occur in hundreds of genes important for various cellular processes, while their insertion and expansion in noncoding regions are associated with neurodegeneration, particularly with subtypes of spinocerebellar ataxia and familial adult myoclonic epilepsy. We describe a new striking domain-swapped DNA–DNA interaction triggered by the addition of divalent cations, including Mg$^{2+}$ and Ca$^{2+}$. The results of NMR characterization of d(ATTTC)$_3$ in solution show that the oligonucleotide folds into a novel 3D architecture with two central C:C$^+$ base pairs sandwiched between a couple of T:T base pairs. This structural element, referred to here as the TCCTzip, is characterized by intercalative hydrogen-bonding, while the nucleobase moieties are poorly stacked. The 5′- and 3′-ends of TCCTzip motif are connected by stem-loop segments characterized by A:T base pairs and stacking interactions. Insights embodied in the non-canonical DNA structure are expected to advance our understanding of why only certain pyrimidine-rich DNA repeats appear to be pathogenic, while others can occur in the human genome without any harmful consequences.

• Language: English
• Keywords: chemical biology, nucleic acid chemistry, DNA, epilepsy
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 1591–1601
• Numbering: Vol. 52, iss. 4
• PID: 20.500.12556/RUL-164639
• UDC: 577
• ISSN on article: 1362-4962
• DOI: 10.1093/nar/gkae052
• COBISS.SI-ID: 189426435
• Publication date in RUL: 06.11.2024

Record is a part of a journal

• Title: Nucleic acids research (Online)
• Shortened title: Nucleic acids res. online
• Publisher: Oxford University Press, Nucleic Acids Research
• ISSN: 1362-4962
• COBISS.SI-ID: 2172954

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: biokemija, DNK, genomi, epilepsija

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0242
• Name: Kemija in struktura bioloških učinkovin

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: J1-1704
• Name: Strukture štirivijačnih nukleinskih kislin s tandemskimi ponovitvami