Damage-induced LncRNAs Control the DNA Damage Response Through Interaction with DDRNAs at Individual Double-strand Breaks

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2017 Nov 29

PMID 29180822

Citations 193

Authors

Flavia Michelini

Sethuramasundaram Pitchiaya

Valerio Vitelli

Sheetal Sharma

Ubaldo Gioia

Fabio Pessina

Matteo Cabrini

Yejun Wang

Ilaria Capozzo

Fabio Iannelli

Valentina Matti

Sofia Francia

G V Shivashankar

Nils G Walter

Fabrizio dAdda di Fagagna

Affiliations

Soon will be listed here.

Abstract

The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends. DilncRNAs act both as DDRNA precursors and by recruiting DDRNAs through RNA-RNA pairing. Together, dilncRNAs and DDRNAs fuel DDR focus formation and associate with 53BP1. Accordingly, inhibition of RNAPII prevents DDRNA recruitment, DDR activation and DNA repair. Antisense oligonucleotides matching dilncRNAs and DDRNAs impair site-specific DDR focus formation and DNA repair. We propose that DDR signalling sites, in addition to sharing a common pool of proteins, individually host a unique set of site-specific RNAs necessary for DDR activation.

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