Loss of TAF8 causes TFIID dysfunction and p53-mediated apoptotic neuronal cell death

Date

2022

Authors

El-Saafin, F.
Bergamasco, M.I.
Chen, Y.
May, R.E.
Esakky, P.
Hediyeh-zadeh, S.
Dixon, M.
Wilcox, S.
Davis, M.J.
Strasser, A.

Editors

Advisors

Journal Title

Journal ISSN

Volume Title

Type:

Journal article

Citation

Cell Death and Differentiation, 2022; 29(5):1013-1027

Statement of Responsibility

Farrah El-Saafin, Maria I. Bergamasco, Yunshun Chen, Rose E. May, Prabagaran Esakky, Soroor Hediyeh-zadeh, Mathew Dixon, Stephen Wilcox, Melissa J. Davis, Andreas Strasser, Gordon K. Smyth, Tim Thomas, and Anne K. Voss

Conference Name

DOI

10.1038/s41418-022-00982-5

Abstract

Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo.

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Copyright © 2022, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare

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Grant ID

http://purl.org/au-research/grants/nhmrc/215301
 http://purl.org/au-research/grants/nhmrc/1084504
 http://purl.org/au-research/grants/nhmrc/1016701
 http://purl.org/au-research/grants/nhmrc/1003435
 http://purl.org/au-research/grants/nhmrc/575512
 http://purl.org/au-research/grants/nhmrc/1081421
 http://purl.org/au-research/grants/nhmrc/1020363
 http://purl.org/au-research/grants/nhmrc/1154970
 http://purl.org/au-research/grants/nhmrc/1176789
 http://purl.org/au-research/grants/nhmrc/1176199

Published Version

https://doi.org/10.1038/s41418-022-00982-5

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Persistent link to this record

https://hdl.handle.net/2440/135444