Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

Abstract

SUMMARY Homologous recombination is a universal process, conserved from bacteriophage to human, which is important for the repair of double-strand DNA breaks. Recombination in mitochondrial DNA (mtDNA) was documented more than 4 decades ago, but the underlying molecular mechanism has remained elusive. Recent studies have revealed the presence of a Rad52-type recombination system of bacteriophage origin in mitochondria, which operates by a single-strand annealing mechanism independent of the canonical RecA/Rad51-type recombinases. Increasing evidence supports the notion that, like in bacteriophages, mtDNA inheritance is a coordinated interplay between recombination, repair, and replication. These findings could have profound implications for understanding the mechanism of mtDNA inheritance and the generation of mtDNA deletions in aging cells.

DNA Sequences Proximal to Human Mitochondrial DNA Deletion Breakpoints Prevalent in Human Disease Form G-quadruplexes, a Class of DNA Structures Inefficiently Unwound by the Mitochondrial Replicative Twinkle Helicase

“…Understanding the molecular-genetic basis for the accumulation of mtDNA mutations remains an active area of study. Two prominent models for the accumulation of mtDNA deletions with aging are: 1) replication slippage over repeated sequences (55) and 2) homologous recombination repair of double strand breaks (32). G-quadruplex DNA, which perturbs the progression of the mtDNA replication machinery, may contribute to either mechanism by causing stalling during DNA synthesis and/or double strand break formation during processing of replication intermediates.…”

“…The site-specific mitochondrial deletions associated with PMPS and other mitochondrial disorders (KSS and PEO) are characterized by direct repeats of 8 -13 bp present in the normal mitochondrial genome, which flank the deletion breakpoints (29 -31). It has been proposed that homologous recombination may be responsible for the direct repeat signature pattern characteristic of PMPS and other sporadic mtDNA deletion disorders (32). The common 4977-bp deletion flanked by a 13-bp repeat in the normal mtDNA sequence frequently identified in sporadic PEO and other mitochondrial disorders (33) is characterized by a 5Ј breakpoint at mtDNA position 8468 bp, which resides in a predicted G4-forming sequence according to the Pattern Finder algorithm.…”

Eukaryotic DNA Polymerases in Homologous Recombination

“…It functions in the replication and repair of mitochondrial DNA (18, 58). Recent evidence suggests that HR is utilized to repair DSBs in mitochondrial DNA in budding yeast and to a limited extent in mammals (18).…”

Mitochondrial DNA maintenance: an appraisal

“…The potential role of other DNA repair mechanisms, such as mismatch repair and DNA break repair in mtDNA maintenance, has been recently reviewed in several excellent papers [23, 143,[165][166][167]177].…”