When two kinases are better than one

When two kinases are better than one V idal-Eychenié et al. describe how two protein kinases team up to respond to DNA damage at stalled replication forks. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes the repair of DNA double-strand breaks (DSBs) by nonhomologous end joining (NHEJ). The ATR kinase, on the other hand, initiates cell cycle arrest and DNA repair after recognizing the long stretches of single-stranded DNA (ssDNA) that accumulate when replication forks are delayed. In cancer cells, which are under increased replicative stress, stalled rep-lication forks collapse to generate DSBs as well as ssDNA, but whether DNA-PKcs and ATR cooperate to initiate a DNA damage response at these lesions is unknown. Vidal-Eychenié et al. emulated the damage at collapsed repli-cation forks by designing DNA fragments containing a short stretch of ssDNA and double-stranded ends that mimic DSBs. These fragments induced a robust DNA damage response when incubated in cell-free extracts, but this response was blocked by inhibitors of both DNA-PKcs and ATR. DNA-PKcs enhanced ATR's activity by phosphorylating two proteins—RPA32 and TopBP1—that aid the kinase's recruitment and activation on short stretches of ssDNA. This might help ATR respond immediately to replication catastrophes. ATR, in turn, promoted the phosphorylation of DNA-PKcs at a site that might cause the kinase to favor the repair of DSBs by homologous recombination instead of NHEJ, thereby reducing genome instability. DNA-PKcs and ATR therefore act synergisti-cally to respond to replication-associated damage in cancer cells. Senior author Angelos Constantinou says that inhibitors of this pathway could be used to selectively target tumor cells in vivo. A protein associated with the neuro developmental disorder lissencephaly promotes the assembly of dynein–dynactin motor complexes on mRNA cargoes, Dix et al. reveal. Many mRNAs are transported to specifi c locations within the cell so that the proteins they encode are synthesized in the right place. In early Droso-phila embryos, for example, certain mRNAs are transported to the apical cytoplasm by the minus end–directed microtubule-based motor dynein and its accessory complex dynactin. Dynein and dynactin are recruited to their cargo by adaptor proteins that bind to a " localization signal " in the mRNA. How the assembly and function of the motor complex are regulated is unclear, however. Dix et al. found that the dynein-associated protein Lis1 was recruited to the localization signals of several Drosophila mRNAs. Fly embryos with reduced levels of Lis1 were defective in transporting these mRNAs …