HGNC Approved Gene Symbol: ATRIP
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:48,446,737-48,467,645 (from NCBI)
Cortez et al. (2001) searched for substrates of ATM (see 607585) and ATR (601215) and identified a protein of 86 kD, which they called ATRIP for 'ATR-interacting protein.' The full-length cDNA encodes a deduced 791-amino acid protein with a coiled-coil domain near its N terminus. RNA blotting indicated that ATRIP is expressed in all tissues tested. Cortez et al. (2001) also identified an alternatively spliced exon encoding amino acids 658 to 684 near the C-terminus. RT-PCR from 2 cell lines indicated that both forms were expressed.
ATRIP is phosphorylated by ATR, regulates ATR expression, and is an essential component of the DNA damage checkpoint pathway. Cortez et al. (2001) demonstrated that ATR and ATRIP both localize to intranuclear foci after DNA damage or inhibition of replication. Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death. Therefore, ATR is essential for the viability of human somatic cells. Small interfering RNA directed against ATRIP caused the loss of both ATRIP and ATR expression and the loss of checkpoint responses to DNA damage. Cortez et al. (2001) concluded that ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways.
The function of the ATR-ATRIP protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Zou and Elledge (2003) demonstrated that replication protein A (RPA) complex, which associates with single-stranded DNA (ssDNA), is required for recruitment of ATR to sites of DNA damage and for ATR-mediated CHK1 (603078) activation in human cells. In vitro, RPA stimulates the binding of ATRIP to single-stranded DNA. The binding of ATRIP to RPA-coated single-stranded DNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the RAD17 (603139) protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-stranded DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, is defective for recruiting Ddc2 to single-stranded DNA both in vivo and in vitro. Zou and Elledge (2003) concluded that RPA-coated single-stranded DNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.
By mutation analysis, Namiki and Zou (2006) identified 2 major RPA-ssDNA-interacting domains of ATRIP in regions flanking the conserved coiled-coil domain. They also identified an internal region of ATRIP that exhibited affinity to single-stranded DNA. Namiki and Zou (2006) concluded that there are multiple interactions between ATRIP and RPA-ssDNA and that ATRIP may interact directly with ssDNA in the ATRIP-RPA-ssDNA complex.
For discussion of a possible association between Seckel syndrome (see 210600) and variation in the ATRIP gene, see 606605.0001.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human ATRIP is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
This variant is classified as a variant of unknown significance because its contribution to Seckel syndrome (see 210600) has not been confirmed.
In a patient, born of consanguineous Gujarati-Indian parents, with Seckel syndrome, Ogi et al. (2012) identified a heterozygous c.2278C-T transition in exon 12 of the ATRIP gene, resulting in an arg760-to-ter (R760X) substitution. The unaffected mother also carried the mutation. RT-PCR analysis of patient and parental cells indicated that the c.2278C-T mutation was not subject to nonsense-mediated mRNA decay (NMD) and that the paternal allele carried a splicing defect affecting exon 2 that was likely subject to NMD. Based on mRNA levels, the patient was estimated to have about 25% of residual wildtype ATRIP activity; Western blot analysis showed 10 to 20% residual protein levels and decreased ATR (601215). Studies of patient cells and in vitro functional expression studies showed that the R760X mutation did not promote ATR-dependent G2/M cell cycle arrest after UV radiation and reduced the ATR-ATRIP interaction, consistent with a loss of function. The patient had severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism. The clinical and cellular phenotype was similar to that observed in Seckel patients with ATR mutations.
Cortez, D., Guntuku, S., Qin, J., Elledge, S. J. ATR and ATRIP: partners in checkpoint signaling. Science 294: 1713-1716, 2001. [PubMed: 11721054] [Full Text: https://doi.org/10.1126/science.1065521]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Namiki, Y., Zou, L. ATRIP associates with replication protein A-coated ssDNA through multiple interactions. Proc. Nat. Acad. Sci. 103: 580-585, 2006. [PubMed: 16407120] [Full Text: https://doi.org/10.1073/pnas.0510223103]
Ogi, T., Walker, S., Stiff, T., Hobson, E., Limsirichaikul, S., Carpenter, G., Prescott, K., Suri, M., Byrd, P. J., Matsuse, M., Mitsutake, N., Nakazawa, Y., Vasudevan, P., Barrow, M., Stewart, G. S., Taylor, A. M. R., O'Driscoll, M., Jeggo, P. A. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel syndrome. PLoS Genet. 8: e1002945, 2012. Note: Electronic Article. [PubMed: 23144622] [Full Text: https://doi.org/10.1371/journal.pgen.1002945]
Zou, L., Elledge, S. J. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300: 1542-1548, 2003. [PubMed: 12791985] [Full Text: https://doi.org/10.1126/science.1083430]