Suchergebnisse

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers. ; Work in MPC lab is supported by Liverpool University, Newcastle University and a Wellcome Institutional Support Fund Award. Work done in A.G.'s lab was supported by Bulgarian National Science Fund grant # DN11/17. Work in the PP lab is supported by grants from the Agence Nationale pour la Recherche (ANR), the Ligue Contre le Cancer (équipe labellisée), SIRIC Montpellier Cancer (INCa Inserm DGOS 12553) and the MSDAvenir fund. ULM was funded by the Royal Society RG170342. IHL was funded from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 754510. Work in the DR lab is supported by a Wellcome Trust Seed Award in Science (206103/Z/17/Z). Work of JMGH was funded by a Wellcome Trust Investigator Award [106951/Z/15/Z] and a Royal Society Wolfson Research Merit Award

1. The Strategic Plan for Biodiversity (2011–2020), adopted at the 10th meeting of the Conference of the Parties to the Convention on Biological Diversity, sets 20 Aichi Biodiversity Targets to be met by 2020 to address biodiversity loss and ensure its sustainable and equitable use. Aichi Biodiversity Target 11 describes what an improved conservation network would look like for marine, terrestrial and inland water areas, including freshwater ecosystems. 2. To date, there is no comprehensive assessment of what needs to be achieved to meet Target 11 for freshwater biodiversity. Reports on implementation often fail to consider explicitly freshwater ecosystem processes and habitats, the pressures upon them, and therefore the full range of requirements and actions needed to sustain them. 3. Here the current progress and key gaps for meeting Aichi Target 11 are assessed by exploring the implications of each of its clauses for freshwater biodiversity. 4. Concerted action on Aichi Biodiversity Target 11 for freshwater biodiversity by 2020 is required in a number of areas: a robust baseline is needed for each of the clauses described here at national and global scales; designation of new protected areas or expansion of existing protected areas to cover known areas of importance for biodiversity and ecosystem services, and a representative sample of biodiversity; use of Other Effective Area-Based Conservation Measures (OECMs) in places where designating a protected area is not appropriate; and promoting and implementing better management strategies for fresh water in protected areas that consider its inherent connectivity, contextual vulnerability, and required human and technical capacity. 5. Considering the specific requirements of freshwater systems through Aichi Biodiversity Target 11 has longterm value to the Sustainable Development Goals discussions and global conservation policy agenda into the coming decades. ; VH was funded by a Ramon y Cajal contract (RYC-2013-13979) funded by the Spanish government. IH is grateful to Conservation International for funding his contributions to the 2014 World Parks Congress; the Department of Ichthyology, American Museum of Natural History, New York for granting Research Associate status; and Columbia University, New York for granting Adjunct Research Scientist Status, and allowing access to their library facilities. SL was funded by an ARC DECRA grant DE130100565.