Two ways to condense

Two ways to condense G ene-rich euchromatin and largely untranscribed heterochromatin may follow different rules to prepare for mitosis, according to J. Robert Manak, Joseph Lipsick, and colleagues (Stanford University, Stanford, CA). From S phase to prophase, chromatin must replicate and then condense to prepare for mitosis. In most eukaryotic cells, euchromatin starts the process by replicating fi rst, but it is the last to condense. Heterochromatin is sandwiched in between, opening for replication and then condensing straightaway. Proper condensation, the authors find, requires Myb, a fl y kinase that regulates S phase. Fly cells lacking Myb divided normally for about a dozen cycles but then began to arrest in prophase with condensation errors. “They start to condense,” says Lipsick, “but they can’t fi nish.” The failure, the group found, lay in euchromatin. Condensation was normal in heterochromatin but failed to spread to euchromatin. Myb was normally found on euchromatin, where it may maintain histone modifi cations that drive condensation either directly or via other proteins. Lipsick thinks that cells might use a separate mechanism to make sure that heterochromatin condenses immediately after it replicates. “Heterochromatin is mostly composed of transposons,” he says. “Like a computer virus, its goal is to make more copies of itself. It might be to a cell’s advantage to keep it turned off whenever possible.” Reference: Manak, J.R., et al. 2007. Nat. Cell Biol. doi:10.1038/ncb1580. Checkpoint yin and yang U biquitin fl ips the switch for spindle checkpoint inactivation, according to a pair of studies by Sashank Reddy, Marc Kirschner, and colleagues and by Frank Stegmeier, Stephen Elledge (Harvard Medical School, Boston, MA), and colleagues. The checkpoint stands guard over mitosis to ensure accurate chromosome segregation. While the spindle takes time to assemble, two checkpoint proteins bind tightly to Cdc20 to keep it from activating the anaphase-promoting complex (APC). The checkpoint stays on as long as it senses that kinetochores are still unattached. The researchers found that fl ooding the system with UbcH10, which ubiquitinates APC, or p31comet, a protein previously implicated in checkpoint inactivation, caused cells to crash through the checkpoint. These proteins promoted APC-dependent ubiquitination of Cdc20, which pried it from the checkpoint proteins’ grip and released the brake on anaphase. An RNAi screen in the Elledge lab uncovered a deubiquitinating enzyme, called USP44, that provides the opposing force to keep the checkpoint on. High levels of USP44 caused cells to arrest in mitosis. Without it, cells divided rampantly with chromosome segregation errors. These opposing forces determine the ultimate level of Cdc20 ubiquitination. Only when Cdc20 is suffi ciently ubiquitinated can anaphase procede. Many tumors have elevated levels of UbcH10, which might push them prematurely into anaphase. References: Reddy, S.K., et al. 2007. Nature. 446:921–925. Stegmeier, F., et al. 2007. Nature. 446:876–881.