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Foiani M.,Fondazione Istituto di Oncologia Molecolare | Foiani M.,University of Milan | Bartek J.,Danish Cancer Society | Bartek J.,Palacky University
Cell | Year: 2014

The Golgi apparatus consists of disc-like cisternae, stretching around the nucleus through forces exerted by F-actin and the Golgi membrane protein GOLPH3. Farber-Katz et al. now report that DNA damage triggers Golgi dispersal and inhibits vesicular transport through DNA-PK-mediated GOLPH3 phosphorylation, thereby linking the DNA damage response to Golgi regulation. © 2014 Elsevier Inc.

Wollscheid H.-P.,Fondazione Istituto di Oncologia Molecolare
Nature Structural and Molecular Biology | Year: 2016

Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VIshort and myosin VIlong, which differ in the C-terminal region. Their physiological and pathological roles remain unknown. Here we identified an isoform-specific regulatory helix, named the α2-linker, that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the α2-linker structurally defines a new clathrin-binding domain that is unique to myosin VIlong and masks the known RRL interaction motif. This finding is relevant to ovarian cancer, in which alternative myosin VI splicing is aberrantly regulated, and exon skipping dictates cell addiction to myosin VIshort in tumor-cell migration. The RRL interactor optineurin contributes to this process by selectively binding myosin VIshort. Thus, the α2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VIlong) or migratory (myosin VIshort) functional roles. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Bermejo R.,Fondazione Istituto di Oncologia Molecolare | Capra T.,Fondazione Istituto di Oncologia Molecolare | Jossen R.,Fondazione Istituto di Oncologia Molecolare | Colosio A.,Fondazione Istituto di Oncologia Molecolare | And 12 more authors.
Cell | Year: 2011

Transcription hinders replication fork progression and stability, and the Mec1/ATR checkpoint protects fork integrity. Examining checkpoint-dependent mechanisms controlling fork stability, we find that fork reversal and dormant origin firing due to checkpoint defects are rescued in checkpoint mutants lacking THO, TREX-2, or inner-basket nucleoporins. Gene gating tethers transcribed genes to the nuclear periphery and is counteracted by checkpoint kinases through phosphorylation of nucleoporins such as Mlp1. Checkpoint mutants fail to detach transcribed genes from nuclear pores, thus generating topological impediments for incoming forks. Releasing this topological complexity by introducing a double-strand break between a fork and a transcribed unit prevents fork collapse. Mlp1 mutants mimicking constitutive checkpoint-dependent phosphorylation also alleviate checkpoint defects. We propose that the checkpoint assists fork progression and stability at transcribed genes by phosphorylating key nucleoporins and counteracting gene gating, thus neutralizing the topological tension generated at nuclear pore gated genes. © 2011 Elsevier Inc.

Lai M.S.,Fondazione Istituto di Oncologia Molecolare | Foiani M.,Fondazione Istituto di Oncologia Molecolare | Foiani M.,University of Milan
Cell | Year: 2012

The ATR and ATM checkpoint kinases preserve the integrity of replicating chromosomes by preventing the reversal of stalled and terminal replication forks. Hu et al. now show that the ATR pathway targets the Dna2 nuclease to process stalled forks and counteract fork reversal. © 2012 Elsevier Inc.

Ferrari E.,Fondazione Istituto di Oncologia Molecolare | Lucca C.,Fondazione Istituto di Oncologia Molecolare | Foiani M.,Fondazione Istituto di Oncologia Molecolare | Foiani M.,University of Milan
European Journal of Cancer | Year: 2010

In recent years, cancer drug discovery has faced the challenging task of integrating the huge amount of information coming from the genomic studies with the need of developing highly selective target-based strategies within the context of tumour cells that experience massive genome instability. The combination between genetic and genomic technologies has been extremely useful and has contributed to efficiently transfer certain approaches typical of basic science to drug discover projects. An example comes from the synthetic lethal approaches, very powerful procedures that employ the rational used by geneticists working on model organisms. Applying the synthetic lethality (SL) screenings to anticancer therapy allows exploiting the typical features of tumour cells, such as genome instability, without changing them, as opposed to the conventional anticancer strategies that aim at counteracting the oncogenic signalling pathways. Recent and very encouraging clinical studies clearly show that certain promising anticancer compounds work through a synthetic lethal mechanism by targeting pathways that are specifically essential for the viability of cancer cells but not of normal cells. Herein we describe the rationale of the synthetic lethality approaches and the potential applications for anticancer therapy. © 2010 Elsevier Ltd. All rights reserved.

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