Polµ deficiency increases resistance to oxidative damage and delays liver aging.

Polµ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polµ (Polµ(-/-)) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polµ(-/-) mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polµ(-/-) deficiency on liver aging. We found that old Polµ(-/-) mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polµ(-/-) liver showed reduced genomic instability and increased apoptosis resistance. However, Polµ(-/-) mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polµ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.

A novel method for biodosimetry.

Accurate methods for measuring the biological effects of radiation are critical for estimating an individual's health risk from radiation exposure. We investigated the feasibility of using radiation-induced mutations in repetitive DNA sequences to measure genetic damage caused by radiation exposure. Most repetitive sequences are in non-coding regions of the genome and alterations in these loci are usually not deleterious. Thus, mutations in non-coding repetitive sequences might accumulate, providing a stable molecular record of DNA damage caused by all past exposures. To test this hypothesis, we screened repetitive DNA sequences to identify the loci most sensitive to radiation-induced mutations and then investigated whether these mutations were stable in vivo over time and after multiple exposures. Microsatellite repeat markers were identified that exhibited a linear dose response up to 1 Gy of 1 GeV/nucleon 56Fe ions and 137Cs gamma rays in mouse and human cells. Short tandem repeats on the Y chromosome and mononucleotide repeats on autosomal chromosomes exhibited significant increases in mutations at >or= 0.5 Gy of 56Fe ions with frequencies averaging 4.3-10.3 x 10(-3) mutations/locus/Gy/cell, high enough for direct detection of mutations in irradiated cells. A significant increase in radiation-induced mutations in extended mononucleotide repeats was detectible in vivo in mouse blood and cheek samples 10 and 26 weeks after radiation exposure and these mutations were additive over multiple exposures. This study demonstrates the feasibility of a novel method for biodosimetry that is applicable to humans and other species. This new approach should complement existing methods of biodosimetry and might be useful for measuring radiation exposure in circumstances that are not amenable to current methods.