Journal
NUCLEIC ACIDS RESEARCH
Volume 37, Issue 7, Pages 2327-2335Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkp091
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Funding
- Medical Research Council
- Wellcome Trust
- European Union Framework 6 Integrated Programme - EU Mitocombat
- National Institutes of Health [AG021905, AG17994, AG21042]
- MRC [G0500695, MC_U105663140] Funding Source: UKRI
- Medical Research Council [G0500695, MC_U105663140] Funding Source: researchfish
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Expression of a proof-reading deficient form of mitochondrial DNA (mtDNA) polymerase , POLG, causes early death accompanied by features of premature ageing in mouse. However, the mechanism of cellular senescence remains unresolved. In addition to high levels of point mutations of mtDNA, the POLG mutator mouse harbours linear mtDNAs. Using one- and two-dimensional agarose gel electrophoresis, we show that the linear mtDNAs derive from replication intermediates and are indicative of replication pausing and chromosomal breakage at the accompanying fragile sites. Replication fork arrest is not random but occurs at specific sites close to two cis-elements known as O-H and O-L. Pausing at these sites may be enhanced in the case of exonuclease-deficient POLG owing to delayed resumption of DNA replication, or replisome instability. In either case, the mtDNA replication cycle is perturbed and this might explain the progeroid features of the POLG mutator mouse.
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