期刊
JOURNAL OF CELL SCIENCE
卷 129, 期 7, 页码 1468-1476出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.182188
关键词
DICER; DNA damage response; DROSHA; Non-coding RNA
类别
资金
- Fondazione Italiana per la Ricerca sul Cancro, AIRC [12971]
- Human Frontier Science Program Cariplo Foundation [RGP 0014/2012, 2010.0818, 2014-1215]
- Marie Curie Initial Training Networks [FP7 PEOPLE ITN (CodAge)]
- Fondazione Telethon [GGP12059]
- Progetti di Ricerca di Interesse Nazionale (PRIN)
- Italian Ministry of Education Universities and Research EPIGEN Project
- European Research Council advanced grant [322726]
- Worldwide Cancer Research (Association for International Cancer Research) [14-1331]
- Collegio Ghislieri
- European Research Council (ERC) [322726] Funding Source: European Research Council (ERC)
The DNA damage response (DDR) plays a central role in preserving genome integrity. Recently, we reported that the endoribonucleases DICER and DROSHA contribute to DDR activation by generating small non-coding RNAs, termed DNA damage response RNA (DDRNA), carrying the sequence of the damaged locus. It is presently unclear whether DDRNAs act by promoting the primary recognition of DNA lesions or the secondary recruitment of DDR factors into cytologically detectable foci and consequent signal amplification. Here, we demonstrate that DICER and DROSHA are dispensable for primary recruitment of the DDR sensor NBS1 to DNA damage sites. Instead, the accumulation of the DDR mediators MDC1 and 53BP1 (also known as TP53BP1), markers of secondary recruitment, is reduced in DICER- or DROSHA-inactivated cells. In addition, NBS1 (also known as NBN) primary recruitment is resistant to RNA degradation, consistent with the notion that RNA is dispensable for primary recognition of DNA lesions. We propose that DICER, DROSHA and DDRNAs act in the response to DNA damage after primary recognition of DNA lesions and, together with gamma H2AX, are essential for enabling the secondary recruitment of DDR factors and fuel the amplification of DDR signaling.
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