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

Roopa Thapar, Jing L. Wang, Michal Hammel, Ruiqiong Ye, Ke Liang, Chengcao Sun, Ales Hnizda, Shikang Liang, Su S. Maw, Linda Lee, Heather Villarreal, Isaac Forrester, Shujuan Fang, Miaw Sheue Tsai, Tom L. Blundell, Anthony J. Davis, Chunru Lin, Susan P. Lees-Miller, Terence R. Strick, John A. Tainer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10953-10972
Number of pages20
JournalNucleic acids research
Volume48
Issue number19
DOIs
StatePublished - Nov 4 2020

ASJC Scopus subject areas

  • Genetics

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