Mitochondrial DNA deletions are associated with non-B DNA conformations

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Joana Damas (Author) Other; Joao Carneiro (Author) Other; Joana Goncalves (Author) Other; James B Stewart (Author) Other; David C Samuels (Author) Other; Antonio Amorim (Author) FCUP; Filipe Pereira (Author) Other

Journal

Title: Nucleic Acids Research

Vol. 40

Pages: 7606-7621

ISSN: 0305-1048

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 48 Citations

Scopus - 48 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-002-62T

DOI: 10.1093/nar/gks500

Abstract (EN): Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are believed to contribute to the aging process and to various neurodegenerative diseases. Despite strong observational and experimental evidence, the molecular basis of the deletion process remains obscure. In this study, we test the hypothesis that the primary cause of mtDNA vulnerability to breakage resides in the formation of non-B DNA conformations, namely hairpin, cruciform and cloverleaf-like elements. Using the largest database of human mtDNA deletions built thus far (753 different cases), we show that site-specific breakage hotspots exist in the mtDNA. Furthermore, we discover that the most frequent deletion breakpoints occur within or near predicted structures, a result that is supported by data from transgenic mice with mitochondrial disease. There is also a significant association between the folding energy of an mtDNA region and the number of breakpoints that it harbours. In particular, two clusters of hairpins (near the D-loop 3'-terminus and the L-strand origin of replication) are hotspots for mtDNA breakage. Consistent with our hypothesis, the highest number of 5'- and 3'-breakpoints per base is found in the highly structured tRNA genes. Overall, the data presented in this study suggest that non-B DNA conformations are a key element of the mtDNA deletion process.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16