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Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment

ABSTRACT: We implicated the X-chromosome THOC2 gene, which encodes largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically variable neurodevelopmental disorder with intellectual disability as the core phenotype. To study how compromised function of this essential eukaryotic gene leads to NDD outcomes, we generated a clinically-relevant mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Sushma Rao

LAB HEAD: Raman Sharma

PROVIDER: PXD040358 | Pride | 2024-02-12

REPOSITORIES: Pride

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			Action	DRS
	20230123_074006_Thoc2Del-UoA-DIA-ExtLibAdded_ProteinReport.xls	Xls
	SDRF-22022023.txt	Txt
	Thoc2Del-UoA-DIA-E18_5-3ul-Hemi-1_RA5_1_4298.d.zip	Other
	Thoc2Del-UoA-DIA-E18_5-3ul-Hemi-4_RA8_1_4299.d.zip	Other
	Thoc2Del-UoA-DIA-E18_5-Hemi-1_RA5_1_4286.d.zip	Other

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Compromised THOC2, a TREX mRNA export complex scaffold protein, leads to R-loop accumulation, DNA damage and adverse neurodevelopmental outcomes in mice and men

Project description:TREX (Transcription-Export) is a highly conserved multi-subunit protein complex that, besides its established role in mRNA export from nucleus to cytoplasm, is involved in transcriptional regulation, stem cell maintenance, 3’ mRNA processing, mitotic progression, and genome stability in eukaryotic cells. TREX is composed of a six subunit THO core complex (THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7) and eight accessory proteins. We have implicated the X-chromosome THOC2 gene, which encodes the scaffold protein of the THO complex, in a clinically variable neurodevelopmental disorder (NDD) with intellectual disability (ID) as the core phenotype. To study the function of this essential eukaryotic gene and the mechanisms underlying its NDD outcomes, we generated a clinically-relevant mouse model based on a hypomorphic Thoc2 exon37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mice brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Differentiated cortical neurons of Thoc2Δ/Y mice show perturbed synaptic and electrophysiological properties underlined by increased DNA damage comparable to the primary cells of patients with THOC2 pathogenic variants. Altogether, our data suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and men, and DNA damage-associated functional alterations are at the root of THOC2 syndrome. Overall, we suggest that THOC2 is a major, conserved player in the efficient resolution of R-loops, a process essential for normal brain development and function.

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