RESEARCH HIGHLIGHTS content or isochore location are IN BRIEF accounted for. The dovetailing of the authors’ experimental and bioinformatic data EVOLUTION provides extremely strong circumstan- tial evidence that L1 insertions Noise minimization in eukaryotic gene expression. decrease gene expression in vivo. Fraser, H. B. et al. PloS Biol. 27 Apr 2004 (doi:10.1371/journal.pbio.0020137) Moreover, this new work tallies with previous findings that gene expression Until now, the functional and evolutionary significance of stochastic is suppressed when full-length L1 (‘noisy’) fluctuations in the rates of protein production was a mys- sequences are inserted into introns. tery.Michael Eisen and colleagues have developed a model of sto- The authors also raise the intrigu- chastic gene expression in yeast to test their hypothesis that genes ing possibility that the mammalian that encode subunits of multiprotein complexes or that cause lethal- genome might have co-opted tran- ity when deleted would be sensitive to such variation. Their estimates scriptional suppression of L1 (which of the noise in protein production for most yeast genes confirm this probably first evolved to prevent hypothesis and indicate that natural selection minimizes noise in excessive mutagenic retrotransposi- gene expression. tion) as a mechanism for fine-tuning the relative levels of expression of dif- CANCER GENETICS ferent genes. If this model is correct, perhaps L1 is better viewed as more Impact of the KU80 pathway on NHEJ-induced of a genomic classroom assistant than genome rearrangements on mammalian cells. Han and colleagues followed up a problematic pupil? Guirouilh-Barbat, J. et al. Mol. Cell 14, 611–623 (2004) their experiments with a neat bit of Nick Campbell bioinformatics. They compared the The genomes of cancer cells are often unstable and undergo rearrange- amount of L1 sequence in the genes References and links ments. Non-homologous end joining (NHEJ), a process that joins ORIGINAL RESEARCH PAPER Han, J. S. et al. with the highest and lowest levels of Transcriptional disruption by the L1 broken ends of double-strand breaks (DSBs) in DNA, is generally expression in humans. The results retrotransposon and implications for mammalian associated with maintaining mammalian genome stability. Josée were striking: highly expressed genes transcriptomes. Nature 429, 268–274 (2004) Guirouilh-Barbat and colleagues now show that NHEJ might occur FURTHER READING Han, J. S. & Boeke, J. D. contained small amounts of L1 sequ- A highly active synthetic mammalian in two-thirds of DSB repairs. Surprisingly, their data indicate that this ence, whereas genes with low levels of retrotransposon. Nature 429, 314–318 (2004) pathway often incorporates broken DNA into new locations and so expression contained large amounts WEB SITE accounts for many genome rearrangements that are seen in cancer cells. Jef Boeke’s laboratory: of L1 sequence. These patterns hold http://www.bs.jhmi.edu/MBG/boekelab/boeke_ even when differences in total intron lab_homepage AGEING Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. idea that PLZF promotes stem-cell maintenance, possibly through Picard, F. et al. Nature 2 June 2004 (doi:10.1038/nature02583) chromatin remodelling. Zfp145–/– germ cells would be channelled Premature ageing in mice expressing defective down the differentiation pathway mitochondrial DNA polymerase. at the expense of proliferating. Trifunovic, A. et al. Nature 429, 417–423 (2004) Indeed, Pandolfi and co-authors show that Zfp145–/– cells do badly Two studies provide separate molecular explanations for the ageing at repopulating testes that lack process in mammals. In yeast, the SIR2 gene is the link between stem cells, probably because so few calorie restriction and an extended lifespan. Leonard Guarente and undifferentiated cells are present. colleagues have now investigated how Sirt1 (sirtuin 1), the mam- Given the roles of PLZF in limb malian version of SIR2,mediates the same effect in the mouse. Fat development, acute-promyelocytic reduction extends the mouse lifespan, and the authors have shown leukaemia and germ stem-cell that this is caused by the ability of SIRT1 to promote fat mobiliza- differentiation, this protein tion in adipocytes by repressing the fat regulator PPAR-γ during provides an interesting link food deprivation. Nils-Göran Larsson and colleagues focussed between development, cancer instead on the mitochondrial DNA (mtDNA), which is known to biology and stem-cell maintenance. accumulate mutations with age. Mice that were defective for the Tanita Casci mtDNA polymerase PolgA — because they expressed a nuclear References and links ORIGINAL RESEARCH PAPERS Buaas, F. W. knock-in mutation that abolished the proofreading ability of the et al. Plzf is required in adult germ cells for stem polymerase — accumulated 3–5 times the number of point muta- cell self-renewal. Nature Genet. 36, 647–652 tions, aged prematurely and developed age-related features, such (2004) | Costoya, J. A., Hobbs, R. M. et al. Essential role of Plzf in maintenance of as baldness and reduced fertility. This clever experiment supports spermatogonial stem cells. Nature Genet. 36, the view that mtDNA mutations are the cause rather than the 653–659 (2004) consequence of ageing. NATURE REVIEWS | GENETICS VOLUME 5 | JULY 2004 | 487.