Mice expressing an error-prone DNA polymerase in mitochondria display elevated replication pausing and chromosomal breakage at fragile sites of mitochondrial DNA.

Abstract:

:Expression of a proof-reading deficient form of mitochondrial DNA (mtDNA) polymerase gamma, 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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Bailey LJ,Cluett TJ,Reyes A,Prolla TA,Poulton J,Leeuwenburgh C,Holt IJ

doi

10.1093/nar/gkp091

subject

Has Abstract

pub_date

2009-04-01 00:00:00

pages

2327-35

issue

7

eissn

0305-1048

issn

1362-4962

pii

gkp091

journal_volume

37

pub_type

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