Alternative titles; symbols
HGNC Approved Gene Symbol: RPA3
Cytogenetic location: 7p21.3 Genomic coordinates (GRCh38): 7:7,636,518-7,718,607 (from NCBI)
Umbricht et al. (1993) cloned RPA3, which is the 14-kD subunit of human RPA, from a HeLa cell cDNA library. The RPA3 gene has a 692-basepair sequence with an open reading frame encoding a protein of 121 amino acids. The deduced amino acid sequence showed only limited similarity to the small subunit of yeast RPA. See also RPA1 (179835) and RPA2 (179836).
The function of the ATR (601215)-ATRIP (606605) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Zou and Elledge (2003) demonstrated that the 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.
Activation-induced cytidine deaminase (AID; 605257) is a ssDNA deaminase required for somatic hypermutation and class switch recombination of immunoglobulin genes. Class switch recombination involves transcription through switch regions, which generates ssDNA within R loops. Chaudhuri et al. (2004) characterized the mechanism of AID targeting to in vitro transcribed substrates harboring somatic hypermutation motifs. They showed that the targeting activity of AID is due to RPA, a ssDNA-binding heterochimeric protein involved in replication, recombination, and repair. The 32-kD subunit of RPA interacts specifically with AID from activated B cells in a manner that seems to be dependent on posttranslational AID modification. Chaudhuri et al. (2004) concluded that RPA is implicated as a novel factor involved in immunoglobulin diversification, and proposed that B cell-specific AID-RPA complexes preferentially bind to ssDNA of small transcription bubbles at somatic hypermutation hotspots, leading to AID-mediated deamination and RPA-mediated recruitment of DNA repair proteins.
Using PCR amplification of genomic DNA from rodent-human hybrid cell lines, Umbricht et al. (1993) mapped the human REPA3 gene to chromosome 7. By Southern analysis and PCR amplification of somatic cell hybrids of chromosome 7, as well as by fluorescence in situ hybridization, Umbricht et al. (1994) mapped RPA3 to 7p22.
Chaudhuri, J., Khuong, C., Alt, F. W. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430: 992-998, 2004. [PubMed: 15273694] [Full Text: https://doi.org/10.1038/nature02821]
Umbricht, C. B., Erdile, L. F., Jabs, E. W., Kelly, T. J. Cloning, overexpression, and genomic mapping of the 14-kDa subunit of human replication protein A. J. Biol. Chem. 268: 6131-6138, 1993. [PubMed: 8454588]
Umbricht, C. B., Griffin, C. A., Hawkins, A. L., Grzeschik, K. H., O'Connell, P., Leach, R., Green, E. D., Kelly, T. J. High-resolution genomic mapping of the three human replication protein A genes (RPA1, RPA2, and RPA3). Genomics 20: 249-257, 1994. [PubMed: 8020972] [Full Text: https://doi.org/10.1006/geno.1994.1161]
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]