The Caenorhabditis elegans LET‐418/Mi2 plays a conserved role in lifespan regulation

Summary The evolutionarily conserved nucleosome‐remodeling protein M i2 is involved in transcriptional repression during development in various model systems, plays a role in embryonic patterning and germ line development, and participates in DNA repair and cell cycle progression. It is the catalytic subunit of the nucleosome remodeling and histone deacetylase ( N u RD ) complex, a key determinant of differentiation in mammalian embryonic stem cells. In addition, the D rosophila and C . elegans M i2 homologs participate in another complex, the MEC complex, which also plays an important developmental role in these organisms. Here we show a new and unexpected feature of the C . elegans M i2 homolog, LET ‐418/ M i2. Lack of LET ‐418/ M i2 results in longevity and enhanced stress resistance, a feature that we found to be conserved in D rosophila and in A rabidopsis . The fact that depletion of other components of the N u RD and the MEC complexes did not result in longevity suggests that LET ‐418 may regulate lifespan in a different molecular context. Genetic interaction studies suggest that let‐418 could act in the germ‐cell‐loss pathway, downstream of kri‐1 and tcer‐1 . On the basis of our data and on previous findings showing a role for let‐418 during development, we propose that LET ‐418/Mi2 could be part of a system that drives development and reproduction with concomitant life‐reducing effects later in life.