Structural polymorphism driven by a register shift in a CGAG-rich region found in the promoter of the neurodevelopmental regulator AUTS2 gene

Novotný, Aleš (author), Plavec, Janez (author), Kocman, Vojč (author)

The AUTS2 gene has been shown to influence brain development by controlling the number of neurons, promoting the growth of axons and dendrites and regulating neuronal migration. The expression of two isoforms of AUTS2 protein is precisely regulated and misregulation of their expression has been correlated with neurodevelopmental delay and autism spectrum disorder. A CGAG-rich region, which includes a putative protein binding site (PPBS), d(AGCGAAAGCACGAA), was found in the promoter region of AUTS2 gene. We show that oligonucleotides from this region adopt thermally stable non-canonical hairpin structures stabilized by G:C and sheared G:A base pairs arranged in a repeating structural motif we termed CGAG block. These motifs are formed consecutively, in a way that exploits a shift in register throughout the whole CGAG repeat to maximize the number of consecutive G:C and G:A base pairs. The differences in CGAG repeat shifting affect the structure of the loop region, where PPBS residues are predominantly located, specifically the loop length, types of base pairs and the pattern of base-base stacking. Finally, we propose a previously unexplored mechanism, by which different folds in the CGAG-rich region could cause a switch in expression between the full-length and C-terminal isoforms of AUTS2.

• Language: English
• Keywords: chemical biology, nucleic acid chemistry, brain development, neurons, proteins, AUTS2
• 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: 2023
• Number of pages: Str. 2602–2613
• Numbering: Vol. 51, iss. 6
• PID: 20.500.12556/RUL-152402
• UDC: 577
• ISSN on article: 1362-4962
• DOI: 10.1093/nar/gkad117
• COBISS.SI-ID: 145972995
• Publication date in RUL: 23.11.2023

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, razvoj možganov, nevroni, proteini, AUTS2