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.
St. Vincent's Institute of Medical Research, Fitzroy, Australia.
Sabine
S
Jurado
Ian
I
Smyth
Bryce
B
van Denderen
Nora
N
Tenis
Andrew
A
Hammet
Kimberly
K
Hewitt
Jane-Lee
JL
Ng
Carolyn J
CJ
McNees
Sergei V
SV
Kozlov
Hayato
H
Oka
Masahiko
M
Kobayashi
Lindus A
LA
Conlan
Timothy J
TJ
Cole
Ken-Ichi
K
Yamamoto
Yoshihito
Y
Taniguchi
Shunichi
S
Takeda
Martin F
MF
Lavin
Jörg
J
Heierhorst
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