Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis.
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 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.
Jurado
Sabine
S
St. Vincent's Institute of Medical Research, Fitzroy, Australia.
Smyth
Ian
I
van Denderen
Bryce
B
Tenis
Nora
N
Hammet
Andrew
A
Hewitt
Kimberly
K
Ng
Jane-Lee
JL
McNees
Carolyn J
CJ
Kozlov
Sergei V
SV
Oka
Hayato
H
Kobayashi
Masahiko
M
Conlan
Lindus A
LA
Cole
Timothy J
TJ
Yamamoto
Ken-Ichi
K
Taniguchi
Yoshihito
Y
Takeda
Shunichi
S
Lavin
Martin F
MF
Heierhorst
Jörg
J
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008168:Lung / Q000196:embryology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D038081:Organogenesis / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D013997:Time Factors; D014132:Trachea / Q000196:embryology; D014157:Transcription Factors; D014466:Ultraviolet Rays
C554480:ATMIN protein, mouse; D002352:Carrier Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D014157:Transcription Factors; D006861:Hydrogen Peroxide