Alternative titles; symbols
HGNC Approved Gene Symbol: PAXIP1
Cytogenetic location: 7q36.2 Genomic coordinates (GRCh38) : 7:154,943,690-155,003,411 (from NCBI)
Using mouse Pax2 (167409) as bait in a yeast 2-hybrid screen of an embryonic mouse cDNA library, Lechner et al. (2000) cloned Paxip1l, which they called Ptip. The deduced 1,056-amino acid protein has a calculated molecular mass of 119.3 kD. Ptip contains 2 N-terminal and 3 C-terminal BRCA1 (113705) (BRCT) domains separated by a glutamine-rich region. Northern blot analysis of mouse tissues detected ubiquitous expression of a 4.0-kb transcript, with highest expression in embryonic kidney and brain. PTIP was also expressed in all human and mouse cell lines examined. In mouse fibroblasts, Ptip localized to the nucleus. Differential solubilization revealed that Ptip fractionated with soluble chromatin and copurified with nuclear matrix proteins under high salt conditions. Western blot analysis detected endogenous mouse Ptip at an apparent molecular mass of 130 kD.
By yeast 2-hybrid analysis and in vitro binding assays, Lechner et al. (2000) found that mouse Ptip bound to the C-terminal transactivation domain of Pax2. Deletions in the C-terminal region of Pax2 containing the partial homeodomain and PSTY-rich domain diminished the interaction in a yeast 2-hybrid assay. The Pax2 octapeptide motif also affected the interaction.
Manke et al. (2003) used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. They identified a tandem BRCT domain in PTIP and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize substrates phosphorylated by the kinases ATM (607585) and ATR (601215) in response to gamma irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1 (605230)- and phospho-H2AX (601772)-containing nuclear foci, a marker of DNA damage. Manke et al. (2003) concluded that their findings provided a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation met1775 to arg (M1775R; 113705.0035), which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer.
To understand the normal cellular function of PTIP, Cho et al. (2007) affinity purified PTIP-associated proteins from nuclear extracts prepared from HeLa cells grown in the absence of DNA damage agent treatment. Mass spectrometry analysis and subsequent purification demonstrated that PTIP associated with ASH2L (604782), RBBP5 (600697), WDR5 (609012), NCOA6 (605299), Set-domain-containing histone methyltransferases MLL3 (606833) and MLL4 (KMT2D; 602113), DPY30 (612032), C16ORF53 (612033), and substoichiometric amount of JmjC domain-containing putative histone demethylase UTX (300128) in a Set1-like complex that carried robust histone H3 (see 602810) lysine-4 (H3K4) methyltransferase activity.
Daniel et al. (2010) showed that activated B cells deficient in the PTIP component of the MLL3-MLL4 complex display impaired trimethylation of histone H3 at lysine-4 (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy chain (Igh; 147100) locus, leading to defective immunoglobulin class switching. Daniel et al. (2010) also showed that PTIP accumulation at double-strand breakpoints contributes to class switch recombination and genome stability independent of Igh switch transcription. Daniel et al. (2010) concluded that their results demonstrated that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to class switch recombination and suggested a nonredundant role for the MLL3-MLL4 complex in altering antibody effector function.
By radiation hybrid analysis and FISH, Lechner et al. (2000) mapped the PAXIP1 gene to chromosome 7q36.
Rademakers et al. (2005) obtained conclusive evidence of linkage of Alzheimer disease with a candidate region of 19.7 cM at 7q36 (see AD10, 609636). Mutation analysis of coding exons of all 29 known genes in the candidate region identified only an exonic silent mutation in the PAXIP1 gene, 38030G-C in the exon 10 genomic sequence, which affected codon 626. The role of the PAXIP1 gene in expression of AD was unclear since the mutation was present in the index family but absent in 3 other families with multiplex AD who potentially shared a common founder with the index family.
Cho et al. (2003) developed mice with a constitutive null Ptip allele. Homozygous mutants were developmentally retarded and disorganized, and they died by embryonic day 9.5 (E9.5). Ptip mutant cells appeared to replicate DNA, but they showed DNA damage preceding nuclear condensation at E7.5 and reduced levels of mitosis and widespread cell death by E8.5. Embryonic fibroblasts and stem cells from Ptip mutants failed to proliferate in culture, suggesting a fundamental defect in cell proliferation. Trophoblast cells from Ptip mutants were more sensitive to DNA-damaging agents. Condensation of chromatin and expression of phosphohistone H3 (see 602810) were also affected in Ptip mutants, and the authors suggested that these effects may underlie the inability of mutants to progress through mitosis.
Cho, E. A., Prindle, M. J., Dressler, G. R. BRCT domain-containing protein PTIP is essential for progression through mitosis. Molec. Cell. Biol. 23: 1666-1673, 2003. [PubMed: 12588986] [Full Text: https://doi.org/10.1128/MCB.23.5.1666-1673.2003]
Cho, Y.-W., Hong, T., Hong, S., Guo, H., Yu, H., Kim, D., Guszcynski, T., Dressler, G. R., Copeland, T. D., Kalkum, M., Ge, K. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J. Biol. Chem. 282: 20395-20406, 2007. [PubMed: 17500065] [Full Text: https://doi.org/10.1074/jbc.M701574200]
Daniel, J. A., Santos, M. A., Wang, Z., Zang, C., Schwab, K. R., Jankovic, M., Filsuf, D., Chen, H.-T., Gazumyan, A., Yamane, A., Cho, Y.-W., Sun, H.-W., Ge, K., Peng, W., Nussenzweig, M. C., Casellas, R., Dressler, G. R., Zhao, K., Nussenzweig, A. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science 329: 917-923, 2010. [PubMed: 20671152] [Full Text: https://doi.org/10.1126/science.1187942]
Lechner, M. S., Levitan, I., Dressler, G. R. PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. Nucleic Acids Res. 28: 2741-2751, 2000. [PubMed: 10908331] [Full Text: https://doi.org/10.1093/nar/28.14.2741]
Manke, I. A., Lowery, D. M., Nguyen, A., Yaffe, M. B. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302: 636-639, 2003. [PubMed: 14576432] [Full Text: https://doi.org/10.1126/science.1088877]
Rademakers, R., Cruts, M., Sleegers, K., Dermaut, B., Theuns, J., Aulchenko, Y., Weckx, S., De Pooter, T., Van den Broeck, M., Corsmit, E., De Rijk, P., Del-Favero, J., van Swieten, J., van Duijn, C. M., Van Broeckhoven, C. Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample. Am. J. Hum. Genet. 77: 643-652, 2005. [PubMed: 16175510] [Full Text: https://doi.org/10.1086/491749]