A breathtaking phenotype: Unexpected roles of the DNA base damage response protein ASCIZ as a key regulator of early lung development

Abstract

The ATM substrate Chk2-interacting Zn 2+ -finger protein (ASCIZ, also known as ATMIN and ZNF822) has previously been reported to be important for the repair of methylating and oxidative DNA damage, and it has also been proposed to regulate the stability and DNA damage-independent activation of the ATM kinase. While the role of the protein in the regulation of ATM remains controversial, two recent ASCIZ mouse knockout papers confirm its role in the DNA base damage response, including oxidative stress resistance in vivo. Similar to other DNA base damage repair proteins, ASCIZ is essential for embryonic development, with lethality of Asciz-null embryos around day E16.5 post conception. Unexpectedly, absence of ASCIZ also leads to severe organ development defects, most notably, complete absence of lungs similar to mutants in Wnt2-2b/b-catenin and FGF10/ FGFR2b signaling pathways. Together with evidence that ASCIZ can activate transcription in vitro, the phenotype indicates that ASCIZ has dual functions as an efficiency factor for DNA base damage repair as well as a key transcriptional regulator of early lung development.

The Novel Zinc Finger Protein dASCIZ Regulates Mitosis in Drosophila via an Essential Role in Dynein Light-Chain Expression

“…However, the SCD also functions as a potent transcription activation domain, and Asciz-deficient mouse models revealed major DNA damage-independent developmental functions as a transcription factor (Jurado et al 2010). Germline knockout of Asciz results in late embryonic lethality with a range of developmental abnormalities (Jurado et al 2010;Kanu et al 2010), including severe foregut separation defects with complete absence of lungs (Jurado et al 2010;Heierhorst et al 2011). The mRNA for dynein light-chain DYNLL1 was the most strongly downregulated transcript (10-fold) in mouse Asciz knockout cells, and similar DYNLL1 reductions were observed in ASCIZdeficient human and chicken cells (Jurado et al 2012a).…”

ATM Substrate Chk2-interacting Zn2+ Finger (ASCIZ) Is a Bi-functional Transcriptional Activator and Feedback Sensor in the Regulation of Dynein Light Chain (DYNLL1) Expression

“…ASCIZ forms DNA damage-induced nuclear foci, and is required for cell survival, specifically in response to lesions repaired by the base excision repair pathway (12)(13)(14)(15), and in this context may function as a tumor suppressor of peripheral B cell lymphomas (16,17). However, complete absence of ASCIZ causes late-embryonic lethality in mice (14,15) with a range of organ development defects, most notably complete absence of lungs (14), that are most likely due to DNA damage-independent functions as a Zn 2ϩ finger (ZnF) transcription factor (14,18 netically conserved transcriptional activator of Dynll1 gene expression as well as a sensor of DYNLL1 protein levels in a novel feedback mechanism for auto-regulated gene expression.…”

Digitor/dASCIZ Has Multiple Roles in Drosophila Development

“…However, it should be noted that the experiments do not rule out that these effects are an indirect consequence of timing defects and/or Cut up dysregulation. In mammals ASCIZ also has several ATM-kinase independent developmental functions and is required for B cell maturation as well as for lung, kidney, and brain organogenesis [60–62]. Some of these defects are a consequence of dynein light chain down regulation [8,35]; however, in other cases the effects have been suggested to be caused by modulation of developmental signaling cascades such as the Wnt pathway [62].…”