7YF7

NMR solution structures of the DNA minidumbbell formed by two ATTTT repeats

Summary for 7YF7

• Entry DOI: 10.2210/pdb7yf7/pdb
• Descriptor: DNA (5'-D(*AP*TP*TP*TP*TP*AP*TP*TP*TP*T)-3'), SODIUM ION (2 entities in total)
• Functional Keywords: minidumbbell, atttt repeats, spinocerebellar ataxia type 37, familial adult myoclonic epilepsy, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 3221.91

Authors

Wan, L.,Li, J.,Guo, P. (deposition date: 2022-07-07, release date: 2023-01-11, Last modification date: 2024-05-15)

Primary citation

Li, J.,Wan, L.,Wang, Y.,Chen, Y.,Lee, H.K.,Lam, S.L.,Guo, P.
Solution Nuclear Magnetic Resonance Structures of ATTTT and ATTTC Pentanucleotide Repeats Associated with SCA37 and FAMEs.
Acs Chem Neurosci, 14:289-299, 2023

PubMed Abstract: Expansions of ATTTT and ATTTC pentanucleotide repeats in the human genome are recently found to be associated with at least seven neurodegenerative diseases, including spinocerebellar ataxia type 37 (SCA37) and familial adult myoclonic epilepsy (FAME) types 1, 2, 3, 4, 6, and 7. The formation of non-B DNA structures during some biological processes is thought as a causative factor for repeat expansions. Yet, the structural basis for these pyrimidine-rich ATTTT and ATTTC repeat expansions remains elusive. In this study, we investigated the solution structures of ATTTT and ATTTC repeats using nuclear magnetic resonance spectroscopy. Here, we reveal that ATTTT and ATTTC repeats can form a highly compact minidumbbell structure at the 5'-end using their first two repeats. The high-resolution structure of two ATTTT repeats was determined, showing a regular TTTTA pentaloop and a quasi TTTT/A pentaloop. Furthermore, the minidumbbell structure could escape from proofreading by the Klenow fragment of DNA polymerase I when it was located at five or more base pairs away from the priming site, leading to a small-scale repeat expansion. Results of this work improve our understanding of ATTTT and ATTTC repeat expansions in SCA37 and FAMEs, and provide high-resolution structural information for rational drug design.

PubMed: 36580663
DOI: 10.1021/acschemneuro.2c00593

Experimental method

SOLUTION NMR