Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis

Jurado, Sabine, Smyth, Ian, van Denderen, Bryce, Tenis, Nora, Hammet, Andrew, Hewitt, Kimberly, Ng, Jane-Lee, McNees, Carolyn J., Kozlov, Sergei V., Oka, Hayato, Kobayashi, Masahiko, Conlan, Lindus A., Cole, Timothy J., Yamamoto, Ken-ichi, Taniguchi, Yoshihito, Takeda, Shunichi, Lavin, Martin F. and Heierhorst, Jörg (2010) Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis. PLoS Genetics, 6 10: e1001170-1-e1001170-13. doi:10.1371/journal.pgen.1001170

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Author Jurado, Sabine
Smyth, Ian
van Denderen, Bryce
Tenis, Nora
Hammet, Andrew
Hewitt, Kimberly
Ng, Jane-Lee
McNees, Carolyn J.
Kozlov, Sergei V.
Oka, Hayato
Kobayashi, Masahiko
Conlan, Lindus A.
Cole, Timothy J.
Yamamoto, Ken-ichi
Taniguchi, Yoshihito
Takeda, Shunichi
Lavin, Martin F.
Heierhorst, Jörg
Title Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
1553-7404
Publication date 2010-10-21
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1001170
Open Access Status DOI
Volume 6
Issue 10
Start page e1001170-1
End page e1001170-13
Total pages 13
Place of publication San Francisco, United States
Publisher Public Library of Science
Collection year 2011
Language eng
Formatted abstract
Zn2+-finger proteins comprise one of the largest protein superfamilies with diverse biological functions. The ATM substrate
Chk2-interacting Zn2+-finger protein (ASCIZ; also known as ATMIN and ZNF822) was originally linked to functions in the
DNA base damage response and has also been proposed to be an essential cofactor of the ATM kinase. Here we show that
absence of ASCIZ leads to p53-independent late-embryonic lethality in mice. Asciz-deficient primary fibroblasts exhibit
increased sensitivity to DNA base damaging agents MMS and H2O2, but Asciz deletion or knock-down does not affect ATM
levels and activation in mouse, chicken, or human cells. Unexpectedly, Asciz-deficient embryos also exhibit severe
respiratory tract defects with complete pulmonary agenesis and severe tracheal atresia. Nkx2.1-expressing respiratory
precursors are still specified in the absence of ASCIZ, but fail to segregate properly within the ventral foregut, and as a
consequence lung buds never form and separation of the trachea from the oesophagus stalls early. Comparison of
phenotypes suggests that ASCIZ functions between Wnt2-2b/ß-catenin and FGF10/FGF-receptor 2b signaling pathways in
the mesodermal/endodermal crosstalk regulating early respiratory development. We also find that ASCIZ can activate
expression of reporter genes via its SQ/TQ-cluster domain in vitro, suggesting that it may exert its developmental functions
as a transcription factor. Altogether, the data indicate that, in addition to its role in the DNA base damage response, ASCIZ
has separate developmental functions as an essential regulator of respiratory organogenesis.  © 2010 Jurado et al.
Keyword Telangiectasia-mutated kinase
Transcription factor SP1
Excision-repair
Polymerase beta
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Formal correction: error in affiliation: There was an error in affiliation 7 for author Martin F. Lavin.
Affiliation 7 should be: Centre for Clinical Research, University of Queensland, Royal Brisbane Hospital, Herston, Australia. Article #e1001170, pp. 1-13

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2011 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 16 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 05 Dec 2010, 00:02:48 EST