Dataset Information

NBS1 facilitates pre-ribosomal RNA biogenesis

ABSTRACT: Mutations of NBS1 gene result in Nijmegen breakage syndrome (NBS), and the gene encodes NBS1 that forms a complex with MRE11 and RAD50 and participates in DNA damage repair. However, the molecular mechanism by which the mutations of NBS1 cause clinical phenotypes of NBS, such as craniofacial dysmorphism, is still unclear. Here, we show that NBS1 localizes at the rDNA loci in the nucleoli and interacts with ribosome RNA (rRNA) transcription machinery including RNA polymerase I (Pol I) and TCOF1. Loss of NBS1 impairs Pol I-dependent transcription of pre-rRNA and induces nucleolar stress. In particular, lacking Nbs1 in mouse neural crest cells not only leads to the reduction of ribosome biogenesis but also craniofacial abnormalities during prenatal development. Moreover, the C-terminus of NBS1 is associated with pre-rRNA and a number of pre-rRNA processing factors, which may also facilitate pre-rRNA maturation. Taken together, our study reveals the functions of NBS1 in rRNA biogenesis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Diploid Cell

SUBMITTER: Man Luo

LAB HEAD: Xiaochun Yu

PROVIDER: PXD056042 | Pride | 2025-09-15

REPOSITORIES: Pride

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Publications

NBS1 facilitates preribosomal RNA biogenesis.

Luo Man M Yu Xiaochun X

Proceedings of the National Academy of Sciences of the United States of America 20250311 11

Mutations in the <i>NBS1</i> gene result in Nijmegen breakage syndrome (NBS), and the gene encodes NBS1 that forms a complex with MRE11 and RAD50 and participates in DNA damage repair. However, the molecular mechanism by which <i>NBS1</i> mutations cause clinical phenotypes of NBS, such as craniofacial dysmorphism, is still unclear. Here, we show that NBS1 localizes at the ribosomal DNA (rDNA) loci in nucleoli and interacts with ribosomal RNA (rRNA) transcription machinery including RNA polymera ...[more]

PMID: 40067889

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Project description:Myriad of craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as ribosome biogenesis. While it is understood that many of these highly tissue-specific malformations are a consequence of defects in cranial neural crest cells (cNCCs), an embryonic cell group that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell type-selectivity of these effects remains largely unknown. Here we show that DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I and Pol II dependent transcriptional arms of ribosome biogenesis, is a key mediator of the nucleolar stress response. Using an in vitro model of Treacher Collins Syndrome (TCS), a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery, we demonstrate that perturbations in ribosomal RNA (rRNA) transcription induce DDX21-mediated surveillance mechanism in cNCCs, leading to DDX21 relocalization from the nucleolus to the nucleoplasm, its eviction from Pol I and Pol II chromatin targets and inhibition of rRNA processing. Importantly, these effects are cell type-selective, cell-autonomous and involve activation of the p53 pathway. We further show that cNCCs are characterized by the inherently high reservoir of p53 mRNA and sensitivity to p53-mediated apoptosis. Remarkably, preventing the loss of DDX21 from nucleolus and chromatin can rescue both the sensitivity to apoptosis and TCS-associated craniofacial phenotypes in vivo. This mechanism is not restricted to TCS, as gene function perturbations linked to other ribosomopathies with craniofacial manifestations also lead to the activation of DDX21 surveillance. Lastly, we provide evidence that inhibition of rRNA synthesis leads to rDNA damage, and furthermore, that rDNA damage is sufficient to activate DDX21 surveillance and elicits tissue-selective and dosage-dependent effects on craniofacial development in vivo.

			Action	DRS
	MSP2400297_LFQ_reviewed.msf	Msf
	MSP2400297_NBSI_1.raw	Raw
	MSP2400297_NBSI_2.raw	Raw
	MSP2400297_NBSI_3.raw	Raw
	MSP2400297_V1.raw	Raw