Mechanism of efficient double-strand break repair by a long non-coding RNA.

Autor:	Thapar R; Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA., Wang JL; Ecole Normale Supérieure, IBENS, CNRS, INSERM, PSL Research University, Paris 75005, France., Hammel M; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd, Berkeley, CA 94720, USA., Ye R; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, University of Calgary, Alberta, T2N 4N1, Canada., Liang K; Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA., Sun C; Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA., Hnizda A; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK., Liang S; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK., Maw SS; Biological Systems and Bioengineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA., Lee L; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, University of Calgary, Alberta, T2N 4N1, Canada., Villarreal H; CryoEM Core at Baylor College of Medicine, Houston, Texas 77030, USA., Forrester I; CryoEM Core at Baylor College of Medicine, Houston, Texas 77030, USA., Fang S; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, University of Calgary, Alberta, T2N 4N1, Canada., Tsai MS; Biological Systems and Bioengineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA., Blundell TL; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK., Davis AJ; Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Lin C; Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA., Lees-Miller SP; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, University of Calgary, Alberta, T2N 4N1, Canada., Strick TR; Ecole Normale Supérieure, IBENS, CNRS, INSERM, PSL Research University, Paris 75005, France.; Programme 'Equipe Labellisée'', Ligue Nationale Contre le Cancer, Paris 75005, France., Tainer JA; Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd, Berkeley, CA 94720, USA.; Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2020 Nov 04; Vol. 48 (19), pp. 10953-10972.
DOI:	10.1093/nar/gkaa784
Abstrakt:	Mechanistic studies in DNA repair have focused on roles of multi-protein DNA complexes, so how long non-coding RNAs (lncRNAs) regulate DNA repair is less well understood. Yet, lncRNA LINP1 is over-expressed in multiple cancers and confers resistance to ionizing radiation and chemotherapeutic drugs. Here, we unveil structural and mechanistic insights into LINP1's ability to facilitate non-homologous end joining (NHEJ). We characterized LINP1 structure and flexibility and analyzed interactions with the NHEJ factor Ku70/Ku80 (Ku) and Ku complexes that direct NHEJ. LINP1 self-assembles into phase-separated condensates via RNA-RNA interactions that reorganize to form filamentous Ku-containing aggregates. Structured motifs in LINP1 bind Ku, promoting Ku multimerization and stabilization of the initial synaptic event for NHEJ. Significantly, LINP1 acts as an effective proxy for PAXX. Collective results reveal how lncRNA effectively replaces a DNA repair protein for efficient NHEJ with implications for development of resistance to cancer therapy. (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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