Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage

Burger, Kaspar; Schlackow, Margarita; Potts, Martin; Hester, Svenja; Mohammed, Shabaz; Gullerová, Monika

doi:10.1083/jcb.201612131

Cited by 86 publications

(92 citation statements)

References 81 publications

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“…Thus, both DDRNA biogenesis and function appear to occur locally. In agreement with this model, the presence of a phosphorylated form of DICER at DNA damage sites has been recently reported, where it mediates 53BP1 foci formation (Burger et al, 2017), (Burger and Gullerova, 2018). …”

Section: Introductionsupporting

confidence: 52%

“…However, whether non-coding RNA processing occurs locally at sites of DNA damage in the nucleoplasm or in the cytoplasm of damaged cells, remained to be addressed. A debate about the possibility that RNA interference factors might be active in the nucleus, was also exacerbated by the fact that DICER has been first shown to be exclusively cytoplasmatic (Much et al, 2016) and then to be recruited to sites of DNA damage in its phosphorylated form (Burger et al, 2017), (Burger and Gullerova, 2018). …”

Section: Discussionmentioning

confidence: 99%

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DROSHA associates to DNA damage sites and is required for DNA repair

Cabrini

Roncador

Galbiati

et al. 2018

Preprint

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The DNA damage response (DDR) is the signaling cascade through which a cell recognizes DNA lesions, and promotes their resolution via the repair pathways of Non-Homologous End Joining (NHEJ), or Homologous Recombination (HR). We recently demonstrated that DROSHA boosts DDR signaling by processing damage-induced long non-coding RNAs into smaller DNA damage response RNAs (DDRNAs). However, the location at which DROSHA exerts its DDR functions, relative to sites of DNA damage, remains unknown.To investigate DROSHA's localization during DDR activation, we used the DiVA cellular system, which allows the controlled induction of several DNA double strand breaks (DSBs) in the human genome. Indeed, by genome wide chromatin immunoprecipitation followed by next generation sequencing, we demonstrate that DROSHA associates with DSBs. In support of this, DSB-recruitment of DROSHA is detectable at the single-cell level by Proximity Ligation Assay between DROSHA and known DDR markers, and by DNA damage in situ ligation followed by Proximity Ligation Assay (DI-PLA), which demonstrates proximity of DROSHA to DNA ends. DROSHA recruitment occurs at both genic and inter-genic DSBs, suggesting that its recruitment is independent from ongoing transcription preceding damage generation. DROSHA's recruitment to DNA lesions occurs throughout the cell cycle, and with a preference for NHEJ-prone DSBs. Consistently, inhibition of the HR pathway increases DROSHA recruitment, and DROSHA knock down strongly impairs NHEJ efficiency in a GFP-reporter cellular system for monitoring NHEJ DNA repair. Overall, these results demonstrate that DROSHA acts locally at sites of DNA damage to promote NHEJ DNA repair.

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Section: Introductionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

DROSHA associates to DNA damage sites and is required for DNA repair

Cabrini

Roncador

Galbiati

et al. 2018

Preprint

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“…A more recent study showed that Dicer is phosphorylated at position S1016 in the platform‐PIWI/Argonaute/Zwille‐connector helix cassette upon induction of DSBs and recruited to DSB sites to facilitate DDR. Dicer deficiency leads to impaired recruitment of repair factors MDC1 and 53BP1 . This is the first report on phosphorylation‐induced nuclear localisation of Dicer in human cells.…”

Section: Dicer In Maintenance Of Genome Integritymentioning

confidence: 72%

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

2018

Self Cite

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MicroRNAs (miRNAs) are small regulatory noncoding RNAs that are generated in the canonical RNA interference (RNAi) pathway. Drosha, DiGeorge syndrome critical region 8 (DGCR8) and Dicer are key players in miRNA biogenesis. Argonaute (Ago) proteins bind to miRNAs and are guided by them to find messenger RNA targets and carry out post-transcriptional silencing of protein-coding genes. Recently, emerging evidence suggests that RNAi factors have a range of noncanonical functions that are beyond miRNA biogenesis. These functions pertain to various biological processes, such as development, transcriptional regulation, RNA processing and maintenance of genome integrity. Here, we review recent literature reporting miRNA-independent, noncanonical functions of Drosha, DGCR8, Dicer and Ago proteins and discuss the importance of these functions.

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“…In this context, nuclear accumulation is likely driven by increased phosphorylation or inhibition of dephosphorylation at Ser1712 and Ser1836. Studies in human transformed cells reveal that DICER1 phosphorylation at S1728 and S1852 is required in DNA damage response, and nuclear accumulation was driven by an additional phosphorylation at Ser1016 mediated by ATM/ATR (19). During DNA damage response, phosphorylation at Ser1016 likely delays/prevents nuclear export of Dicer1, independent of dephosphorylation at Ser1712 and Ser1836, resulting in nuclear accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…In all of these cases, phosphorylation of Dicer1 was coupled with its translocation from the cytoplasm to the nucleus (18). Burger et al (19) identified an additional serine that is phosphorylated by ATM/ ATR during DNA damage response, resulting in translocation of Dicer1 from cytoplasm to the nucleus in cultured human cells. These results suggest that phosphorylation of Dicer1 is a conserved event; however, the role of Dicer1 phosphorylation and dephosphorylation in vivo in mammals remains unknown.…”

mentioning

confidence: 99%

Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo

Aryal

Pant

Parker-Thornburg

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans. Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether phosphorylation of Dicer1 has a role in mammalian development remains unknown. To investigate the consequence of constitutive phosphorylation, we generated phosphomimetic knock-in mouse models by replacing conserved serines 1712 and 1836 with aspartic acids individually or together. Dicer1S1836D/S1836D mice display highly penetrant postnatal lethality, and the few survivors display accelerated aging and infertility. Homozygous dual-phosphomimetic Dicer1 augments these defects, alters metabolism-associated miRNAs, and causes a hypermetabolic phenotype. Thus, constitutive phosphorylation of Dicer1 results in multiple pathologic processes in mice, indicating that phosphorylation tightly regulates Dicer1 function and activity in mammals.

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Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage

Abstract: Recent work implicated human Dicer in the DNA damage response. Burger et al. show that DNA damage induces phosphorylation of Dicer and promotes DNA repair in the nucleus.

Cited by 86 publications

References 81 publications

DROSHA associates to DNA damage sites and is required for DNA repair

DROSHA associates to DNA damage sites and is required for DNA repair

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo

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