Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks

被引：282

作者：

Michelini, Flavia ^{[1
]}

Pitchiaya, Sethuramasundaram ^{[2
,3
,6
]}

Vitelli, Valerio ^{[1
]}

Sharma, Sheetal ^{[1
]}

Gioia, Ubaldo ^{[1
]}

Pessina, Fabio ^{[1
]}

Cabrini, Matteo ^{[4
]}

Wang, Yejun ^{[5
]}

Capozzo, Ilaria ^{[4
]}

Iannelli, Fabio ^{[1
]}

Matti, Valentina ^{[1
]}

Francia, Sofia ^{[1
,4
]}

Shivashankar, G. V. ^{[1
,5
]}

Walter, Nils G. ^{[2
,3
]}

di Fagagna, Fabrizio d'Adda ^{[1
,4
]}

机构：

[1] IFOM, I-20139 Milan, Italy

[2] Univ Michigan, Dept Chem, Single Mol Anal Grp, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Ctr RNA Biomed, Dept Chem, Ann Arbor, MI 48109 USA

[4] CNR, Ist Genet Mol, I-27100 Pavia, Italy

[5] Natl Univ Singapore, Mechanobiol Inst, Singapore 117411, Singapore

[6] Univ Michigan, Ctr Canc, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

来源：

NATURE CELL BIOLOGY | 2017年 / 19卷 / 12期

基金：

欧洲研究理事会;

关键词：

RNA-POLYMERASE-II; HOMOLOGOUS RECOMBINATION; DIRECTED REPAIR; NASCENT RNA; CHROMATIN; RESOLUTION; PATHWAY; TRANSCRIPTION; GENOME; DICER;

D O I：

10.1038/ncb3643

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1400 / +

页数：29

共 56 条

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