An early warning system for DNA damage

A close look at cerebellar learning he cerebellum handles many motor coordination and reflexive behaviors, and learned adaptations of these behaviors are thought to require synaptic long-term depression (LTD). On page 295, Feil et al. identify a signaling pathway essential for LTD in cerebellar Purkinje cells but, surprisingly, this pathway is required only for a subset of motor reflex adaptations. Using a conditional gene knockout approach, the authors disrupted the expression of cGMP-dependent protein kinase type I (cGKI) in Purkinje cells, which normally express high levels of the kinase. The disruption virtually abolishes cerebellar LTD in the mutant mice, but the animals perform normally in several tests of motor coordination. However, adaptation of the vestibulo-ocular reflex of the mutant mice, which keeps images stable on the retina during head movements, is defective. Feil et al. propose that cGKI links nitric oxide and cGMP signaling to phosphatase inhibition and AMPA receptor endocytosis, leading to synaptic LTD and motor learning. The behavioral results imply that LTD is only required for specific forms of motor learning, though, and not for general motor coordination. The authors are now trying to test their molecular model by conditionally deleting other components of the proposed signaling pathway. ᭿ T Gross cerebellar structure is fine without LTD. yelination involves a vast spreading of cell membrane, but the mechanism underlying this is largely unknown. On page 397, Chun et al. show that laminin-2 induces cell spreading in oligodendrocytes, the myelinating cells of the CNS, by signaling through ␤ 1 integrins and integrin-linked kinase (ILK). They also resolve an apparent difference between mice and humans. In previous studies, humans with a defect in the laminin-2 gene have shown abnormalities in both the peripheral and central nervous systems, whereas laminin-2 mutant mice appeared to have only peripheral myelination defects. In the new study the authors show that, contrary to M An early warning system for DNA damage n page 245, Stokes and Michael show that when DNA damage is present, not only is the replication checkpoint system activated, but an additional system directly notifies replication forks of the problem. Previous work had identified two mechanisms of damage-induced replication arrest, the checkpoint system and a general slowing of fork progression, but the new work uncovers a third mechanism. After observing that alkylation-damaged DNA induces a checkpoint independent block to undamaged DNA replication in Xenopus laevis extracts, the authors found that the damaged …