I’m sitting in an auditorium listening to a seminar by Laura Niedernhoefer from U. Pittsburgh. She’s telling us that Ercc1-/- mice, which are deficient in nucleotide excision repair, show transcriptional changes that mirror those found in old wildtype or unusually long-lived mutant animals. Her data is strongly reminiscent of recent findings that progeroid DNA repair mutants exhibit transcriptional similarities to aging calorie-restricted and dwarf animals. As in the earlier studies, the Ercc1-/- animals showed a marked downregulation of the somatotroph (GH/IGF-I) axis — suggesting that persistent DNA damage causes the body to direct energy away toward repair and away from growth.

Curiously, the Ercc1-/- mice are resistant to both cancer initiation and tumor progression — they rarely form tumors of their own, and even whopping doses of aggressive fibrosarcoma cells (from ERCC1 wildtype animals) don’t result in significant tumor growth. Largely on the basis of the latter finding, Niedernhoefer attributes the decrease in cancer to the downregulation of somatotrophic signaling; the idea here is that tumors can’t get off the ground without the cocktail of growth factors present in an animal with a normal GH/IGF-I axis.

The final chapter of the talk dealt with the mechanism of the ERCC1/XPF nuclease (an obligate heterodimer of the two proteins). Knockout animals showed a specific defect in accurately resolved experimentally induced double-stranded breaks with 3′ overhangs — other sorts of DSBs were processed equally efficiently in wildtype and knockout cells. Genetic crosses with other DSB repair mutants demonstrate that ERCC1 nuclease acts at a different step than either DNA-PKCS or Ku, two other key factors in the cellular response to DSBs.

Niedernhoefer concluded her talk with the provocative idea that DNA cross-links in real cells (as opposed to cells in an experimental setting) are largely the consequence of molecular species formed by lipid peroxidation: reactive oxygen species (ROS) oxidize polyunsaturated membrane lipids, which then fragment into reasonably stable multifunctional unsaturated compounds that are much more stable than the parent ROS and therefore more likely to make it to the nucleus, where they can modify DNA to form cross-links. Consistent with this, diets high in polyunsaturated fats dramatically decrease the lifespan of ERCC1 mutants (which are sensitive to all kinds of DNA cross-links).