2020
DOI: 10.1038/s41467-019-13981-x
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Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

Abstract: Induction of DNA double-strand breaks (DSBs) in ribosomal DNA (rDNA) repeats is associated with ATM-dependent repression of ribosomal RNA synthesis and large-scale reorganization of nucleolar architecture, but the signaling events that regulate these responses are largely elusive. Here we show that the nucleolar response to rDNA breaks is dependent on both ATM and ATR activity. We further demonstrate that ATM-and NBS1-dependent recruitment of TOPBP1 in the nucleoli is required for inhibition of ribosomal RNA s… Show more

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Cited by 70 publications
(160 citation statements)
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“…This conclusion was further supported by appearance of a subset of DSB foci associated with nucleolar markers (colocalization of 53BP1 foci with fibrillarin and UBF in Figure 6A and Supplementary Figure S6A–C ), suggesting that a subset of these breaks occurred within the rDNA itself. It is well established that persistent DSBs correlate with nucleolar disruption ( 32 , 67–69 ).…”
Section: Resultsmentioning
confidence: 99%
“…This conclusion was further supported by appearance of a subset of DSB foci associated with nucleolar markers (colocalization of 53BP1 foci with fibrillarin and UBF in Figure 6A and Supplementary Figure S6A–C ), suggesting that a subset of these breaks occurred within the rDNA itself. It is well established that persistent DSBs correlate with nucleolar disruption ( 32 , 67–69 ).…”
Section: Resultsmentioning
confidence: 99%
“…However, we conducted flow cytometry for cell-cycle analyses and found no significant difference in the syntheses phase between TopBP1 shRNA and control cells. More importantly, depletion of TopBP1 did result in less DNA repair and increased cell apoptosis and DNA damage [23,27]. Taken together, the main function of TopBP1 in PCa is preventing DNA damage instead of promoting DNA replication.…”
Section: Discussionmentioning
confidence: 96%
“…Moreover, two lines of evidence point towards a direct role of JMJD6 in rDNA breaks management: Firstly, JMJD6 is recruited to DNA breaks induced in the nucleolus. Secondly, JMJD6 physically interacts with TCOF1, a nucleolar protein whose function in rDNA breaks management is proven [ 12 , 14 , 28 ].…”
Section: Discussionmentioning
confidence: 99%
“…We tested the mRNA levels of several repair proteins and none of them were significantly affected in JMJD6 KO cells (S6A Fig). In addition, the expression and localization of two essential components of the cellular response to nucleolus DNA damage, NBS1 and Treacle [12,14,28] are not altered (S6B and S6C Fig). Moreover, two lines of evidence point towards a direct role of JMJD6 in rDNA breaks management: Firstly, JMJD6 is recruited to DNA breaks induced in the nucleolus.…”
Section: Plos Geneticsmentioning
confidence: 99%
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