A direct role for small non-coding RNAs in DNA damage response

RTT107 (ESC4, YHR154W) encodes a BRCA1 C-terminal domain protein that is important for recovery from DNA damage during S phase. Rtt107 is a substrate of the checkpoint kinase Mec1, and it forms complexes with DNA repair enzymes, including the nuclease subunit Slx4, but the role of Rtt107 in the DNA damage response remains unclear. We find that Rtt107 interacts with chromatin when cells are treated with compounds that cause replication forks to arrest. This damage-dependent chromatin binding requires the acetyltransferase Rtt109, but it does not require acetylation of the known Rtt109 target, histone H3-K56. Chromatin binding of Rtt107 also requires the cullin Rtt101, which seems to play a direct role in Rtt107 recruitment, because the two proteins are found in complex with each other. Finally, we provide evidence that Rtt107 is bound at or near stalled replication forks in vivo. Together, these results indicate that Rtt109, Rtt101, and Rtt107, which genetic evidence suggests are functionally related, form a DNA damage response pathway that recruits Rtt107 complexes to damaged or stalled replication forks.

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TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response

Cells ◽

10.3390/cells9051186 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1186 ◽

Cited By ~ 1

Author(s):

Sandra Pisonero-Vaquero ◽

Chiara Soldati ◽

Marcella Cesana ◽

Andrea Ballabio ◽

Diego Luis Medina

Keyword(s):

Dna Damage ◽

Cancer Cell ◽

Dna Damage Response ◽

Cell Types ◽

Dependent Manner ◽

Cancer Cell Growth ◽

Direct Role ◽

Growth And Survival ◽

Damage Response ◽

P21 Waf1

The MiT/TFE family of transcription factors (MITF, TFE3, and TFEB), which control transcriptional programs for autophagy and lysosome biogenesis have emerged as regulators of energy metabolism in cancer. Thus, their activation increases lysosomal catabolic function to sustain cancer cell growth and survival in stress conditions. Here, we found that TFEB depletion dramatically reduces basal expression levels of the cyclin-dependent kinase (CDK) inhibitor p21/WAF1 in various cell types. Conversely, TFEB overexpression increases p21 in a p53-dependent manner. Furthermore, induction of DNA damage using doxorubicin induces TFEB-mediated activation of p21, delays G2/M phase arrest, and promotes cell survival. Pharmacological inhibition of p21, instead, abrogates TFEB-mediated protection during the DNA damage response. Together, our findings uncover a novel and direct role of TFEB in the regulation of p21 expression in both steady-state conditions and during the induction of DNA-damage response (DDR). Our observations might open novel therapeutic strategies to promote cancer cell death by targeting the TFEB-p21 pathway in the presence of genotoxic agents.

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Identification of Intermediate-Size Non-Coding RNAs Involved in the UV-Induced DNA Damage Response in C. elegans

PLoS ONE ◽

10.1371/journal.pone.0048066 ◽

2012 ◽

Vol 7 (11) ◽

pp. e48066 ◽

Cited By ~ 5

Author(s):

Aqian Li ◽

Guifeng Wei ◽

Yunfei Wang ◽

Ying Zhou ◽

Xian-en Zhang ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

C Elegans ◽

Damage Response ◽

Intermediate Size ◽

Non Coding Rnas

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Impact of stainless-steel welding fumes on proteins and non-coding RNAs regulating DNA damage response in the respiratory tract of Sprague-Dawley rats

Journal of Toxicology and Environmental Health Part A ◽

10.1080/15287394.2018.1550027 ◽

2018 ◽

Vol 81 (24) ◽

pp. 1231-1245 ◽

Cited By ~ 1

Author(s):

Jayaraman Krishnaraj ◽

Abdul Basit Baba ◽

Periasamy Viswanathan ◽

Veeran Veeravarmal ◽

Viswalingam Balasubramanian ◽

...

Keyword(s):

Dna Damage ◽

Stainless Steel ◽

Respiratory Tract ◽

Dna Damage Response ◽

Welding Fumes ◽

Sprague Dawley ◽

Stainless Steel Welding ◽

Sprague Dawley Rats ◽

Damage Response ◽

Non Coding Rnas

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DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

Nature Communications ◽

10.1038/ncomms13980 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 34

Author(s):

Francesca Rossiello ◽

Julio Aguado ◽

Sara Sepe ◽

Fabio Iannelli ◽

Quan Nguyen ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Cultured Cells ◽

Telomeric Dna ◽

Cellular Events ◽

Mouse Tissues ◽

Damage Response ◽

Dna Strands ◽

Non Coding Rnas

Abstract The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.

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The histone demethylase LSD1/KDM1A promotes the DNA damage response

The Journal of Cell Biology ◽

10.1083/jcb.201302092 ◽

2013 ◽

Vol 203 (3) ◽

pp. 457-470 ◽

Cited By ~ 61

Author(s):

Nima Mosammaparast ◽

Haeyoung Kim ◽

Benoit Laurent ◽

Yu Zhao ◽

Hui Jun Lim ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Ubiquitin Ligase ◽

Histone Demethylase ◽

Dependent Manner ◽

Γ Irradiation ◽

Histone Demethylation ◽

Direct Role ◽

Damage Response ◽

Histone Ubiquitylation

Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to γ-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.

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Distinct and Coordinated Regulation of Small Non-coding RNAs by E2f1 and p53 During Drosophila Development and in Response to DNA Damage

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.695311 ◽

2021 ◽

Vol 9 ◽

Author(s):

Dong Li ◽

Ying Ge ◽

Ze Zhao ◽

Rui Zhu ◽

Xiang Wang ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Critical Role ◽

Small Rna Sequencing ◽

Dynamic Mode ◽

Binding Motif ◽

X Ray ◽

Small Ncrnas ◽

Damage Response ◽

Non Coding Rnas

Small non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), play a pivotal role in biological processes. A comprehensive quantitative reference of small ncRNAs expression during development and in DNA damage response (DDR) would significantly advance our understanding of their roles. In this study, we systemically analyzed the expression profile of miRNAs and piRNAs in wild-type flies, e2f1 mutant, p53 mutant and e2f1 p53 double mutant during development and after X-ray irradiation. By using small RNA sequencing and bioinformatic analysis, we found that both miRNAs and piRNAs were expressed in a dynamic mode and formed 4 distinct clusters during development. Notably, the expression pattern of miRNAs and piRNAs was changed in e2f1 mutant at multiple developmental stages, while retained in p53 mutant, indicating a critical role of E2f1 played in mediating small ncRNAs expression. Moreover, we identified differentially expressed (DE) small ncRNAs in e2f1 mutant and p53 mutant after X-ray irradiation. Furthermore, we mapped the binding motif of E2f1 and p53 around the small ncRNAs. Our data suggested that E2f1 and p53 work differently yet coordinately to regulate small ncRNAs expression, and E2f1 may play a major role to regulate miRNAs during development and after X-ray irradiation. Collectively, our results provide comprehensive characterization of small ncRNAs, as well as the regulatory roles of E2f1 and p53 in small ncRNAs expression, during development and in DNA damage response, which reveal new insights into the small ncRNAs biology.

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