Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders
Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2020
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| Online Access: | https://hdl.handle.net/1721.1/126251 |
| _version_ | 1826198260920877056 |
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| author | Calo, Eliezer Gu, Bo Bowen, Margot E. Aryan, Fardin Zalc, Antoine Liang, Jialiang Flynn, Ryan A. Swigut, Tomek Chang, Howard Y. Attardi, Laura D. Wysocka, Joanna |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Calo, Eliezer Gu, Bo Bowen, Margot E. Aryan, Fardin Zalc, Antoine Liang, Jialiang Flynn, Ryan A. Swigut, Tomek Chang, Howard Y. Attardi, Laura D. Wysocka, Joanna |
| author_sort | Calo, Eliezer |
| collection | MIT |
| description | Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Taken together, our findings illustrate how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations. |
| first_indexed | 2024-09-23T11:02:00Z |
| format | Article |
| id | mit-1721.1/126251 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:02:00Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1262512022-09-27T16:41:02Z Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders Calo, Eliezer Gu, Bo Bowen, Margot E. Aryan, Fardin Zalc, Antoine Liang, Jialiang Flynn, Ryan A. Swigut, Tomek Chang, Howard Y. Attardi, Laura D. Wysocka, Joanna Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Taken together, our findings illustrate how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations. 2020-07-17T20:11:10Z 2020-07-17T20:11:10Z 2018-01 2016-11 2019-12-02T14:44:03Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 https://hdl.handle.net/1721.1/126251 Calo, E. et al. "Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders." Nature 554, 7690 (January 2018): 112–117 © 2018 Springer Nature en http://dx.doi.org/10.1038/nature25449 Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Calo, Eliezer Gu, Bo Bowen, Margot E. Aryan, Fardin Zalc, Antoine Liang, Jialiang Flynn, Ryan A. Swigut, Tomek Chang, Howard Y. Attardi, Laura D. Wysocka, Joanna Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders |
| title | Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders |
| title_full | Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders |
| title_fullStr | Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders |
| title_full_unstemmed | Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders |
| title_short | Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders |
| title_sort | tissue selective effects of nucleolar stress and rdna damage in developmental disorders |
| url | https://hdl.handle.net/1721.1/126251 |
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