ATMIN (ATM Interactor)

2014-07-01   Jörg Heierhorst  

St. Vincents Institute of Medical Research,, Department of Medicine St Vincents Hospital, The University of Melbourne, 9 Princes Street, Fitzroy, Victoria 3065, Australia

Identity

HGNC
LOCATION
16q23.2
IMAGE
Atlas Image
LEGEND
Diagram 1. Genomic context of the human ASCIZ/ATMIN gene. Numbers indicate the nucleotide positions on chromosome 16 (location 16q23.2). Arrows indicate the 5 to 3 orientation of each gene. Modified from NCBI Map Viewer.
LOCUSID
ALIAS
ASCIZ,ZNF822
FUSION GENES

Abstract

Review on ASCIZ\/ATMIN, with data on DNA\/RNA, on the protein encoded and where the gene is implicated.

DNA/RNA

Atlas Image
Diagram 2. ASCIZ/ATMIN gene structure and main alternative splice isforms. ASCIZ/ATMIN contains 5 exons (A-E, center) that are spliced to two main open reading frames based on NCBI AceView. The lower splice isoform accounts for ~85% of transcripts collected in NCBI AceView and encodes an 823 amino acid residue protein with four N-terminal Zinc-fingers. The upper splice isoforms represent ~15% of transcripts and encodes a 667 residue protein with two N-terminal Zinc-fingers. Protein coding sequences are indicated by black boxes; non-coding exon sequences are indicated by open boxes; the grey part of exon C contains coding sequences when spliced into the 4-Zinc-finger transcript, but is out-of-frame as part of the 2-Zinc-finger transcript. The asterisk indicates an in-frame stop-codon in the 5-UTR of the 2-Zinc-finger isoform. The scale bar on top represents 1 kb per notch.

Description

The human ASCIZ/ATMIN gene contains five exons over 11497 bases. The main transcript results from splicing of exon A, parts of exon C, and exons D and E and gives rise to the "full-length" protein containing 823 amino acids with four Zinc-fingers. Two alternative transcripts - comprising either exon B, part of exon C and exons D and E, or a longer exon C and exons D and E - give rise to a shorter 667-residue protein with only two Zinc-fingers. The mouse ASCIZ gene structure may be simpler with only four exons and single main mRNA encoding an 818-residue protein similar to the human 4-Zinc-finger product.

Transcription

In Northern and Western blot experiments, the two main isoforms of ASCIZ/ATMIN are expressed at relatively similar levels in a wide range of human tissues and all cancer-derived cell lines tested (McNees et al., 2005). Northern blots of various mouse tissues also indicate relatively similar expression levels in a wide range of organs (Jurado et al., 2010).

Pseudogene

Two ASCIZ/ATMIN pseudogenes have been detected on chromosome 9 (LOC643342) and chromosome 12 (LOC100418940).

Proteins

Note

The human ASCIZ protein occurs in two isoforms. The more abundant long isoform contains 823 amino acid residues with a mass of 88.3 kDa. The shorter isoform contains 667 residues with a mass of 72.3 kDa. The two isoforms are identical except that the first 156 residues (including the first two Zinc fingers) of the longer form are missing in the shorter protein. Mouse ASCIZ contains 818 amino acids and is generally similar to the longer human isoform. Human and mouse ASCIZ exhibit atypical electrophoretic mobility on SDS-PAGE Western blots with an apparent mass of ~115 kDa rather than the predicted ~88 kDa (McNees et al., 2005). The aberrant mobility is unlikely to be caused by post-translational modifications, as similar mobility retardation is also observed with bacterially expressed recombinant fragments encompassing the SQ/TQ cluster.
Atlas Image
Diagram 3. Topology of the ASCIZ protein. Only the long form is depicted. The shorter form is identical except for lack of the N-terminal 156 residues including the first two Zinc fingers (ZF). Lollipops indicate the 20 SQ/TQ motifs that are potential ATM/ATR kinase phosphorylation sites, including the 11 TQT motif DYNLL1-binding sites in the transcription activation domain.

Description

ASCIZ contains four (or two in the shorter isoform) C2H2 Zinc-fingers at the N-terminus, a so-called core domain, and a C-terminal transcription activation domain. Human ASCIZ contains 20 potential ATM/ATR kinase phosphorylation sites, most of which are clustered in an SQ/TQ cluster domain coinciding with the transcription activation domain (Heierhorst et al., 2011). 11 of these sites are TQT motifs and represent binding sites for the DYNLL1 protein (Rapali et al., 2011; Jurado et al., 2012a).

Expression

Based on Western blots, the ASCIZ protein is ubiquitously expressed at similar levels in all mouse tissues, with slightly higher levels in brain and testis (Jurado et al., 2010). Protein expression has not been systematically analysed in human tissues but is expected to be similar to mRNA expression profiles by Northern blots suggesting ubiquitous expression (McNees et al., 2005).

Localisation

The ASCIZ protein is predominantly, if not exclusively, located to the nucleus but not the nucleolus (McNees et al., 2005; Kanu and Behrens, 2007). The protein forms discrete sub-nuclear foci after treatment with methylating and oxidating DNA base damaging agents (McNees et al., 2005; Rapali et al., 2011).

Function

ASCIZ was originally identified as an ATM/ATR-substrate and Chk2-interacting protein involved in the DNA base damage response (McNees et al., 2005), and later independently re-isolated as an ATM-interacting protein (Kanu and Behrens, 2007). However, based on recent genetic analyses its main role seems to involve essential developmental functions such as a Zinc-finger transcription factor (Heierhorst et al., 2011).
Knockout mice that completely lack Asciz/Atmin die late during gestation (Jurado et al., 2010; Kanu et al., 2010) and exhibit a range of severe organogenesis defects, including most strikingly a complete absence of lungs (Jurado et al., 2010). An N-ethyl-N-nitrosourea (ENU)-generated mouse mutant, gasping-6, that contains a missense mutations of a Zinc-chelating Cys residue in the third Zinc-finger domain of Asciz/Atmin also dies during late gestation with overall similar phenotypic defects to the Asciz/Atmin null mice, including absent or hypomorphic lungs (Goggolidou et al., 2014). Conditional Asciz/Atmin KO mice generated using B lympoid-specific Cd19-Cre (Loizou et al., 2011) or Mb1-Cre (Jurado et al., 2012b) have reduced peripheral B cell numbers due to increased apoptotic cell death during B cell development in the bone marrow.
The most highly downregulated gene in Asciz-deficient cells is the dynein light chain subunit Dynll1 (Jurado et al., 2012a). Strikingly, DYNLL1 protein can in turn bind to about a dozen individual sites - mostly encompassing TQT motifs - in the ASCIZ transcription activation domain (Rapali et al., 2011; Jurado et al., 2012a) and thereby inhibit its transcriptional activity in a concentration-dependent manner (Jurado et al., 2012a), which provides a feedback mechanism to maintain stable DYNLL1 protein levels. The ability of ASCIZ to regulate expression of and bind to the DYNLL1-like dynein light chain (called Cutup) is conserved in Drosophila (Zaytseva et al., 2014).
The importance of DYNLL1 as an ASCIZ target is highlighted by findings that B cell developmental defects in conditional Mb1-Cre Asciz KO mice can be rescued by ectopic expression of DYNLL1, or simultaneous KO of the pro-apoptotic protein Bim whose activity is inhibited by DYNLL1 (Jurado et al., 2012b). Likewise, in Drosophila, RNAi knockdown of ASCIZ or Cutup lead to similar developmental defects, which in case of dASCIZ RNAi can be rescued by Cutup overexpression (Zaytseva et al., 2014).
The role of ASCIZ in DNA damage responses remains unclear. Loss of ASCIZ leads to increased cell death in response to methylating or oxidating DNA damage in human, mouse and chicken cells (McNees et al., 2005; Oka et al., 2008; Jurado et al., 2010; Kanu et al., 2010), and increased basal IgV gene conversion rates in the chicken DT40 B cell line (Oka et al., 2008). ASCIZ focus formation in response to methylating agents depends on DYNLL1 (Jurado et al., 2012a), but it is not known whether this also involves its transcription factor function. The B cell developmental defect of conditional Asciz/Atmin KO mice could not be rescued by deletion of tp53 or complementation with a pre-arranged B cell receptor transgene (Jurado et al., 2012b), supporting a DNA damage-independent mechanism as cause of the B cell deficiency. ASCIZ was earlier reported to be required for ATM protein stability (and thus termed ATMIN) (Kanu and Behrens, 2007), but this was shown to be incorrect in several subsequent studies (Jurado et al., 2010; Loizou et al., 2011; Zhang et al., 2012). ASCIZ was reported to regulate ATM activation by DNA damage-independent chromatin perturbations (Kanu and Behrens, 2007; Zhang et al., 2012) but this was not confirmed in another study (Jurado et al., 2010).

Homology

ASCIZ protein sequences are highly conserved amongst all vertebrates from fish to mammals (Kanu and Behrens, 2007; Jurado et al., 2012a). The ASCIZ protein is structurally and functionally conserved in Drosophila, where it also contains four N-terminal Zinc-fingers and a TQT-rich C-terminal transcription activation domain, condensed into only 388 amino acid residues (Zaytseva et al., 2014).

Mutations

Note

No specific disease-associated mutations of ASCIZ/ATMIN have so far been reported in humans, but an Asciz/Atmin mis-sense mutation has recently been identified as the cause of the gasping6 (Gpg6) ENU mouse mutant (Goggolidou et al., 2014).

Germinal

The gasping6 mouse mutation was isolated in an ENU mutagenesis screen (Ermakov et al., 2009). Asciz/Atmingpg6 mice exhibit exencephaly, edema and absent or small lungs (Ermakov et al., 2009) and a modest kidney cell polarity defect (Goggolidou et al., 2014). Gpg6 mice contain a point mutation that converts the canonical fourth Zinc-chelating Cys residue in the third Zinc-finger domain to a non-chelating Ser residue (Goggolidou et al., 2014). Dynll1 was the most highly reduced mRNA amongst the analyzed transcripts in affected kidneys (Goggolidou et al., 2014).

Implicated in

Entity name
B cell lymphoma
Note
Cd19-Cre conditional Asciz/Atmin deletion has been reported to cause B cell lymphoma in ~40% of mice (whose genetic background was not specified) before 1 year of age (Loizou et al., 2011), but deletion via Mb1-Cre (which is more efficient than Cd19-Cre during early B lympoid stages) in C57BL/6 mice did not lead to B cell lymphoma until at least 2 years of age (Jurado et al., 2012b). Irrespective of genetic background, no lymphomas were observed when Asciz/Atmin was deleted in earlier haematopoietic stem/progenitor cells via Mx1-Cre (Jurado et al., 2012b) or Vav2-Cre (Cremona and Behrens, 2014).
Entity name
Embryonic development/organogenesis
Note
Germline mutations of Asciz/Atmin in mice lead to late embryonic lethality (Jurado et al., 2010; Kanu et al., 2010; Goggolidou et al., 2014). Mice exhibit exencephaly, complete absence of lungs in the Asciz null mutation or a combination of absent and small lungs in the Asciz/Atmingpg6 point mutant, cardiac defects with oedema, and kidney defects.
Entity name
Haematopoiesis/B cell development
Note
Conditional Asciz/Atmin deletion during early B cell developmental stages in mice in the bone marrow leads to peripheral B cell deficiency, which is more severe with Mb1-Cre (Jurado et al., 2012b) than Cd19-Cre (Loizou et al., 2011). Pan-haematopoietic inducible Asciz/Atmin deletion in adolescent mice via Mx1-Cre also leads to a statistically significant but modest and well tolerated anemia (Jurado et al., 2012b).

Article Bibliography

Pubmed IDLast YearTitleAuthors
238514922014ATM signalling and cancer.Cremona CA et al
192357202009Mouse mutagenesis identifies novel roles for left-right patterning genes in pulmonary, craniofacial, ocular, and limb development.Ermakov A et al
248523692014Atmin mediates kidney morphogenesis by modulating Wnt signaling.Goggolidou P et al
214155972011A breathtaking phenotype: unexpected roles of the DNA base damage response protein ASCIZ as a key regulator of early lung development.Heierhorst J et al
221671982012ATM substrate Chk2-interacting Zn2+ finger (ASCIZ) Is a bi-functional transcriptional activator and feedback sensor in the regulation of dynein light chain (DYNLL1) expression.Jurado S et al
228912722012The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim.Jurado S et al
209759502010Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis.Jurado S et al
175257322007ATMIN defines an NBS1-independent pathway of ATM signalling.Kanu N et al
208899732010The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain.Kanu N et al
215758602011ATMIN is required for maintenance of genomic stability and suppression of B cell lymphoma.Loizou JI et al
159337162005ASCIZ regulates lesion-specific Rad51 focus formation and apoptosis after methylating DNA damage.McNees CJ et al
184337212008DNA damage response protein ASCIZ links base excision repair with immunoglobulin gene conversion.Oka H et al
219715452011LC8 dynein light chain (DYNLL1) binds to the C-terminal domain of ATM-interacting protein (ATMIN/ASCIZ) and regulates its subcellular localization.Rapali P et al
243367472014The novel zinc finger protein dASCIZ regulates mitosis in Drosophila via an essential role in dynein light-chain expression.Zaytseva O et al
232195532012Competition between NBS1 and ATMIN controls ATM signaling pathway choice.Zhang T et al

Other Information

Locus ID:

NCBI: 23300
MIM: 614693
HGNC: 29034
Ensembl: ENSG00000166454

Variants:

dbSNP: 23300
ClinVar: 23300
TCGA: ENSG00000166454
COSMIC: ATMIN

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000166454ENST00000299575O43313
ENSG00000166454ENST00000564241O43313
ENSG00000166454ENST00000565237J3QRX7
ENSG00000166454ENST00000566488O43313

Expression (GTEx)

0
10
20
30
40
50
60

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
383210242024Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma.0
383210242024Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma.0
341481372021ATMIN Suppresses Metastasis by Altering the WNT-Signaling Pathway via PARP1 in MSI-High Colorectal Cancer.4
343214652021MicroRNA-361-5p slows down gliomas development through regulating UBR5 to elevate ATMIN protein expression.4
341481372021ATMIN Suppresses Metastasis by Altering the WNT-Signaling Pathway via PARP1 in MSI-High Colorectal Cancer.4
343214652021MicroRNA-361-5p slows down gliomas development through regulating UBR5 to elevate ATMIN protein expression.4
304145012019Atmin modulates Pkhd1 expression and may mediate Autosomal Recessive Polycystic Kidney Disease (ARPKD) through altered non-canonical Wnt/Planar Cell Polarity (PCP) signalling.9
306993582019PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis.39
314814982019ATMIN Is a Tumor Suppressor Gene in Lung Adenocarcinoma.9
304145012019Atmin modulates Pkhd1 expression and may mediate Autosomal Recessive Polycystic Kidney Disease (ARPKD) through altered non-canonical Wnt/Planar Cell Polarity (PCP) signalling.9
306993582019PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis.39
314814982019ATMIN Is a Tumor Suppressor Gene in Lung Adenocarcinoma.9
280127972017Ataxia-telangiectasia mutated interactor regulates head and neck cancer metastasis via KRas expression.3
286488922017ASCIZ/ATMIN is dispensable for ATM signaling in response to replication stress.7
280127972017Ataxia-telangiectasia mutated interactor regulates head and neck cancer metastasis via KRas expression.3

Citation

Jörg Heierhorst

ATMIN (ATM Interactor)

Atlas Genet Cytogenet Oncol Haematol. 2014-07-01

Online version: http://atlasgeneticsoncology.org/gene/45745/gene-explorer/gene-fusions/meetings/