Tags

Type your tag names separated by a space and hit enter

Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.
Nature 2018; 554(7690):112-117Nat

Abstract

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.

Authors+Show Affiliations

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. David H. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts 02139, USA.Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA.Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.Department of Chemistry, Stanford University, Stanford, California 94305, USA.Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.Center for Personal Dynamic Regulomes, Stanford University, 269 Campus Drive, Stanford, California 94305, USA.Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA. Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA. Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA. Howard Hughes Medical Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29364875

Citation

Calo, Eliezer, et al. "Tissue-selective Effects of Nucleolar Stress and rDNA Damage in Developmental Disorders." Nature, vol. 554, no. 7690, 2018, pp. 112-117.
Calo E, Gu B, Bowen ME, et al. Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders. Nature. 2018;554(7690):112-117.
Calo, E., Gu, B., Bowen, M. E., Aryan, F., Zalc, A., Liang, J., ... Wysocka, J. (2018). Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders. Nature, 554(7690), pp. 112-117. doi:10.1038/nature25449.
Calo E, et al. Tissue-selective Effects of Nucleolar Stress and rDNA Damage in Developmental Disorders. Nature. 2018 02 1;554(7690):112-117. PubMed PMID: 29364875.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders. AU - Calo,Eliezer, AU - Gu,Bo, AU - Bowen,Margot E, AU - Aryan,Fardin, AU - Zalc,Antoine, AU - Liang,Jialiang, AU - Flynn,Ryan A, AU - Swigut,Tomek, AU - Chang,Howard Y, AU - Attardi,Laura D, AU - Wysocka,Joanna, Y1 - 2018/01/24/ PY - 2016/11/01/received PY - 2017/12/11/accepted PY - 2018/1/25/pubmed PY - 2018/5/23/medline PY - 2018/1/25/entrez SP - 112 EP - 117 JF - Nature JO - Nature VL - 554 IS - 7690 N2 - 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/29364875/Tissue_selective_effects_of_nucleolar_stress_and_rDNA_damage_in_developmental_disorders_ L2 - https://doi.org/10.1038/nature25449 DB - PRIME DP - Unbound Medicine ER -