Alternative titles; symbols
HGNC Approved Gene Symbol: RBBP8
SNOMEDCT: 771470001;
Cytogenetic location: 18q11.2 Genomic coordinates (GRCh38) : 18:22,914,139-23,026,486 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q11.2 | Jawad syndrome | 251255 | Autosomal recessive | 3 |
| Pancreatic carcinoma, somatic | 3 | |||
| Seckel syndrome 2 | 606744 | Autosomal recessive | 3 |
Fusco et al. (1998) described the isolation and characterization of a cDNA encoding a polypeptide, named RIM (retinoblastoma-interacting myosin-like), that interacted in a yeast 2-hybrid system as well as in mammalian cells with the retinoblastoma (RB1; 614041) protein. The RIM cDNA predicts an 897-amino acid polypeptide containing 2 leucine zipper motifs, an RB1-binding domain, and a CTBP (see 602618)-binding domain. The RIM protein has weak homology to myosin family (see 160720) proteins throughout its length. Northern blot analysis revealed a ubiquitously expressed 3.6-kb mRNA. Immunoprecipitation experiments revealed that a truncated RIM protein containing amino acids 142-897 interacts with RB1 in mammalian cells.
To understand the mechanism by which interaction between E1A and CTBP results in tumorigenesis-restraining activity, Schaeper et al. (1998) searched for cellular proteins that complex with CTBP. By a yeast 2-hybrid screen and RACE PCR, Schaeper et al. (1998) identified and cloned a CTBP-interacting protein (CTIP). CTIP contains a 5-amino acid motif, the PLDLS motif, that is highly conserved among E1A proteins of all human adenoviruses. CTIP binds to CTBP via the PLDLS motif.
Fusco et al. (1998) mapped the RBBP8 gene to chromosome 18q11.2 by fluorescence in situ hybridization.
Yu et al. (1998) used the Sos recruitment system to screen for proteins that bind to the region of BRCA1 (113705) containing the BRCT domains. Yu et al. (1998) found that the BRCT domains interact in vivo with CTIP, a protein identified on the basis of its association with the CTBP transcriptional corepressor (Schaeper et al., 1998). Yu et al. (1998) concluded that BRCA1 regulates gene expression, at least in part, by modulating CTBP-mediated transcriptional repression. Moreover, Yu et al. (1998) found that the in vivo interaction between BRCA1 and CTIP is completely ablated by each of 3 independent tumor-associated mutations affecting the BRCT motifs of BRCA1. Yu et al. (1998) concluded that BRCA1-CTIP interaction may be required for tumor suppression by BRCA1.
Wong et al. (1998) used yeast 2-hybrid and in vitro biochemical assays to demonstrate that CTIP interacts specifically with the C-terminal segment of human BRCA1 from residues 1602 to 1863. A germline mutation that removes the last 11 amino acids from the C terminus of BRCA1 abolishes not only its transcriptional activation function, but also binding to CTIP.
Li et al. (2000) demonstrated that the BRCA1-associated protein CTIP becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase ATM (see 607585). ATM phosphorylates CTIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CTIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 (126335) upon ionizing radiation. Li et al. (2000) concluded that ATM, by phosphorylating CTIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer.
Yu and Baer (2000) showed that CTIP, like its associated factors, is predominantly a nuclear protein. A subset of the endogenous pool of CTIP polypeptides exists in a protein complex that includes both BRCA1 and BRCA1-associated RING-domain protein (BARD1; 601593). At the protein level, CTIP expression varies with cell cycle progression in a pattern identical to that of BRCA1. Thus, the steady-state levels of CTIP polypeptides, which remain low in resting cells and in G(1) cycling cells, increase dramatically as dividing cells traverse the G(1)/S boundary. In contrast to BRCA1, however, the G(1)/S induction of CTIP expression is mediated primarily by posttranscriptional mechanisms. Yu and Baer (2000) found that the interaction between CTIP and BRCA1 is stable in the face of genotoxic stress elicited by treatment with UV light, adriamycin, or hydrogen peroxide. Yu and Baer (2000) suggested that CTIP can potentially modulate the functions ascribed to BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control.
In a search for novel target genes for microsatellite instability (MSI), Vilkki et al. (2002) studied mutation rates in 14 neutral intronic repeats and compared these rates with those observed in exonic coding repeats of potential MSI target genes. As expected, the length of an intronic mononucleotide repeat correlated positively with the number of slippages for both G/C and A/T repeats. Sequencing showed a significantly increased mutation rate in the exonic A9 repeat of CTIP (25/109 = 22.9%) as compared with similar intronic repeats (p less than or equal to 0.001). Vilkki et al. (2002) concluded that CTIP should be evaluated as an MSI target gene.
Using human and mouse expression plasmids in several protein interaction assays, Sum et al. (2002) identified CTIP and BRCA1 as LMO4 (603129)-binding proteins. LDB1 (603451) also associated with a complex containing LMO4, CTIP, and BRCA1 in transfected human embryonic kidney cells. In functional assays, LMO4 repressed BRCA1-mediated transcriptional activation in both yeast and mammalian cells.
Sartori et al. (2007) demonstrated that the human CTIP protein confers resistance to double-strand break-inducing agents and is recruited to double-strand breaks exclusively in the S and G2 cell cycle phases. Moreover, Sartori et al. (2007) revealed that CTIP is required for double-strand break resection, and thereby for recruitment of replication protein A (see RPA1, 179835) and the protein kinase ATR (601215) to double-strand breaks, and for the ensuing ATR activation. Furthermore, Sartori et al. (2007) established that CTIP physically and functionally interacts with the MRE11 (600814) complex, and that both CTIP and MRE11 are required for efficient homologous recombination. Finally, Sartori et al. (2007) demonstrated that CTIP has sequence homology with Sae2, which is involved in MRE11-dependent double-strand break processing in yeast. Sartori et al. (2007) concluded that their findings established evolutionarily conserved roles for CTIP-like proteins in controlling double-strand break resection, checkpoint signaling, and homologous recombination.
Mimitou and Symington (2008) demonstrated that yeast Exo1 nuclease (606063) and Sgs1 helicase (see 604611) functioned in alternative pathways for double-strand break (DSB) processing. Novel, partially resected intermediates, whose initial generation depended on Sae2, accumulated in yeast lacking both Exo1 and Sgs1 and were poor substrates for homologous recombination. When Sae2 was absent, in addition to Exo1 and Sgs1, homology-dependent repair failed and unprocessed DSBs accumulated. Mimitou and Symington (2008) concluded that there is a 2-step mechanism for DSB processing during homologous recombination, with the Mre11 complex and Sae2 removing a small oligonucleotide from DNA ends to form an early intermediate, followed by processing of this intermediate by Exo1 and/or Sgs1 to generate extensive tracts of single-stranded DNA that serve as a substrate for Rad51 (179617).
Yun and Hiom (2009) identified a role for CTIP in repair of DNA double-strand breaks (DSBs) in the avian B-cell line DT40. They established that CTIP is required not only for repair of DSB by homologous recombination in S/G2 phase but also for microhomology-mediated end joining (MMEJ) in G1. The function of CTIP in homologous recombination, but not MMEJ, is dependent on the phosphorylation of serine residue 327 and recruitment of BRCA1 (113705). Cells expressing CTIP protein that cannot be phosphorylated at ser327 are specifically defective in homologous recombination and have a decreased level of single-stranded DNA after DNA damage, whereas MMEJ remains unaffected. Yun and Hiom (2009) concluded that their data support a model in which phosphorylation of ser327 of CTIP as cells enter S phase and the recruitment of BRCA1 functions as a molecular switch to shift the balance of DSB repair from error-prone DNA end joining to error-free homologous recombination.
Quaye et al. (2009) used microcell-mediated chromosome transfer approach and expression microarray analysis to identify candidate genes that were associated with neoplastic suppression in ovarian cancer (167000) cell lines. In over 1,600 ovarian cancer patients from 3 European population-based studies, they genotyped 68 tagging SNPs from 9 candidate genes and found a significant association between survival and 2 tagging SNPs in the RBBP8 gene, rs4474794 (hazard ratio, 0.85; 95% CI, 0.75-0.95; p = 0.007) and rs9304261 (hazard ratio, 0.83; 95% CI, 0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging SNPs in 314 ovarian tumors identified associations between somatic gene deletions and survival. Thirty-five percent of tumors in 101 informative cases showed LOH for the RBBP8 gene, which was associated with a significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p = 0.001). Quaye et al. (2009) concluded that germline genetic variation and somatic alterations of the RBBP8 gene in tumors are associated with survival in ovarian cancer patients.
In vivo, Helmink et al. (2011) demonstrated that in murine cells the histone protein H2AX (601772) prevents nucleases other than Artemis (605988) from processing hairpin-sealed coding ends; in the absence of H2AX, CtIP can efficiently promote the hairpin opening and resection of DNA ends generated by RAG (see 179615) cleavage. This CtIP-mediated resection is inhibited by gamma-H2AX and by MDC1 (607593), which binds to gamma-H2AX in chromatin flanking DNA double-strand breaks. Moreover, the ataxia-telangiectasia mutated kinase (ATM; 607585) activates antagonistic pathways that modulate this resection. CtIP DNA end resection activity is normally limited to cells at postreplicative stages of the cell cycle, in which it is essential for homology-mediated repair. In G1-phase lymphocytes, DNA ends that are processed by CtIP are not efficiently joined by classical nonhomologous end joining and the joints that do form frequently use microhomologies and show significant chromosomal deletions. Helmink et al. (2011) concluded that H2AX preserves the structural integrity of broken DNA ends in G1-phase lymphocytes, thereby preventing these DNA ends from accessing repair pathways that promote genomic instability.
Robert et al. (2011) showed that histone deacetylase (HDAC) inhibition/ablation specifically counteracts yeast Mec1 (ortholog of human ATR) activation, double-strand break processing, and single-strand DNA-RFA nucleofilament formation. Moreover, the yeast recombination protein Sae2 is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 (see HDAC4, 605314) and Rpd3 (HDAC1; 601241) and 1 histone acetyltransferase (HAT), Gcn5 (GCN5L2; 602301), have key roles in these processes. Robert et al. (2011) also found that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of Hda1 and Rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor (MTOR; 601231), also causes Sae2 degradation. Robert et al. (2011) proposed that Rpd3, Hda1, and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand break processing with autophagy.
In a consanguineous Iraqi family with Seckel syndrome mapping to chromosome 18p11.31-q11.2 (SCKL2; 606744), Qvist et al. (2011) sequenced the candidate gene RBBP8 and identified homozygosity for a splice site mutation (604124.0002) that segregated with the disease was not found in 100 controls. Analysis of RBBP8 in a consanguineous Pakistani family with another microcephaly syndrome mapping to 18p11.22-q11.2 (Jawad syndrome; 251255), Qvist et al. (2011) identified homozygosity for a 2-bp deletion (604124.0003) in affected individuals.
In a 9-year-old Saudi Arabian girl with Seckel syndrome, Shaheen et al. (2014) identified homozygosity for a missense mutation in the RBBP8 gene (R100W; 604124.0004).
Somatic Mutations
Wong et al. (1998) screened a panel of 89 tumor cell line cDNAs for mutations in the CTIP coding region and identified 5 missense variants, including 1 in a pancreatic carcinoma cell line (604124.0001). The authors suggested that CTIP might be a tumor suppressor acting in the same pathway as BRCA1 (113705).
The article by Kaidi et al. (2010) describing interaction between CTIP and SIRT6 (606211) was retracted because an investigation by the University of Cambridge concluded that the first author, Abderrahmane Kaidi, falsified data.
Wong et al. (1998) screened a panel of 89 tumor cell line cDNAs for mutations in the CTIP coding region and identified 5 missense variants. In the pancreatic carcinoma cell line BxPC3, a lysine-to-glutamic acid change at codon 337 was accompanied by apparent loss of heterozygosity or nonexpression of the wildtype allele. Thus Wong et al. (1998) concluded that it is possible that CTIP may itself be a tumor suppressor acting in the same pathway as BRCA1 (113705).
In 4 affected sibs from a consanguineous Iraqi family with Seckel syndrome-2 (SCKL2; 606744), previously studied by Borglum et al. (2001), Qvist et al. (2011) identified homozygosity for a T-G transversion 53 bp within intron 15 of the RBBP8 gene (2347+53T-G), resulting in an alternatively spliced transcript and a C-terminally truncated protein. The unaffected parents were both heterozygous for the splice site mutation, which was not found in 100 controls. Analysis of cell lines from family members demonstrated defective DNA damage-induced formation of single-stranded DNA, which acts as a critical cofactor for ATR (601215) activation; thus, SCKL2 cells present a lower apoptotic threshold and hypersensitivity to DNA damage. Overexpression of a comparable truncated CTIP variant in non-Seckel cells recapitulated SCKL2 cellular phenotypes in a dose-dependent manner. Qvist et al. (2011) stated that this represented a new type of genetic disease mechanism in which a dominant-negative mutation yields a recessively inherited disorder.
In affected members of a consanguineous Pakistani family with microcephaly, mental retardation, and digital anomalies (JWDS; 251255) mapping to chromosome 18p11.22-q11.2, previously studied by Hassan et al. (2008), Qvist et al. (2011) identified homozygosity for a 2-bp deletion in exon 11 of the RBBP8 gene, causing a frameshift resulting in a premature termination codon. The mutation was detected in heterozygosity in 2 obligate carriers and was not found in any controls. Qvist (2012) stated that mutation was 1868delTA.
In a 9-year-old Saudi Arabian girl with Seckel syndrome-2 (SCKL2; 606744), Shaheen et al. (2014) identified homozygosity for a c.298C-T transition in the RBBP8 gene, resulting in an arg100-to-trp (R100W) substitution.
Borglum, A. D., Balslev, T., Haagerup, A., Birkebaek, N., Binderup, H., Kruse, T. A., Hertz, J. M. A new locus for Seckel syndrome on chromosome 18p11.31-q11.2. Europ. J. Hum. Genet. 9: 753-757, 2001. [PubMed: 11781686] [Full Text: https://doi.org/10.1038/sj.ejhg.5200701]
Fusco, C., Reymond, A., Zervos, A. S. Molecular cloning and characterization of a novel retinoblastoma-binding protein. Genomics 51: 351-358, 1998. [PubMed: 9721205] [Full Text: https://doi.org/10.1006/geno.1998.5368]
Hassan, M. J., Chishti, M. S., Jamal, S. M., Tariq, M., Ahmad, W. A syndromic form of autosomal recessive congenital microcephaly (Jawad syndrome) maps to chromosome 18p11.22-q11.2. Hum. Genet. 123: 77-82, 2008. [PubMed: 18071751] [Full Text: https://doi.org/10.1007/s00439-007-0452-x]
Helmink, B. A., Tubbs, A. T., Dorsett, Y., Bednarski, J. J., Walker, L. M., Feng, Z., Sharma, G. G., McKinnon, P. J., Zhang, J., Bassing, C. H., Sleckman, B. P. H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes. Nature 469: 245-249, 2011. Note: Erratum: Nature 472: 247 only, 2011. [PubMed: 21160476] [Full Text: https://doi.org/10.1038/nature09585]
Kaidi, A., Weinert, B. T., Choudhary, C., Jackson, S. P. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329: 1348-1353, 2010. Note: Editorial Expression of Concern: Science 361: 1322 only, 2018. Retraction: Science 364: 247 only, 2019. [PubMed: 20829486] [Full Text: https://doi.org/10.1126/science.1192049]
Li, S., Ting, N. S. Y., Zheng, L., Chen, P.-L., Ziv, Y., Shiloh, Y., Lee, E. Y.-H. P., Lee, W.-H. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406: 210-215, 2000. [PubMed: 10910365] [Full Text: https://doi.org/10.1038/35018134]
Mimitou, E. P., Symington, L. S. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455: 770-774, 2008. [PubMed: 18806779] [Full Text: https://doi.org/10.1038/nature07312]
Quaye, L., Dafou, D., Ramus, S. J., Song, H., Gentry-Maharaj, A., Notaridou, M., Hogdall, E., Kjaer, S. K., Christensen, L., Hogdall, C., Easton, D. F., Jacobs, I., Menon, U., Pharoah, P. D. P., Gayther, S. A. Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival. Hum. Molec. Genet. 18: 1869-1878, 2009. Note: Erratum: Hum. Molec. Genet. 18: 2928 only, 2009. [PubMed: 19270026] [Full Text: https://doi.org/10.1093/hmg/ddp107]
Qvist, P., Huertas, P., Jimeno, S., Nyegaard, M., Hassan, M. J., Jackson, S. P., Borglum, A. D. CtIP mutations cause Seckel and Jawad syndromes. PLoS Genet. 7: e1002310, 2011. Note: Electronic Article. [PubMed: 21998596] [Full Text: https://doi.org/10.1371/journal.pgen.1002310]
Qvist, P. Personal Communication. Aarhus, Denmark 2/21/2012.
Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M. HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature 471: 74-79, 2011. [PubMed: 21368826] [Full Text: https://doi.org/10.1038/nature09803]
Sartori, A. A., Lukas, C., Coates, J., Mistrik, M., Fu, S., Bartek, J., Baer, R., Lukas, J., Jackson, S. P. Human CtIP promotes DNA end resection. Nature 450: 509-514, 2007. [PubMed: 17965729] [Full Text: https://doi.org/10.1038/nature06337]
Schaeper, U., Subramanian, T., Lim, L., Boyd, J. M., Chinnadurai, G. Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif. J. Biol. Chem. 273: 8549-8552, 1998. [PubMed: 9535825] [Full Text: https://doi.org/10.1074/jbc.273.15.8549]
Shaheen, R., Faqeih, E., Ansari, S., Abdel-Salam, G., Al-Hassnan, Z. N., Al-Shidi, T., Alomar, R., Sogaty, S., Alkuraya, F. S. Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Res. 24: 291-299, 2014. [PubMed: 24389050] [Full Text: https://doi.org/10.1101/gr.160572.113]
Sum, E. Y. M., Peng, B., Yu, X., Chen, J., Byrne, J., Lindeman, G. J., Visvader, J. E. The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumor suppressor BRCA1 and inhibits BRCA1 activity. J. Biol. Chem. 277: 7849-7856, 2002. [PubMed: 11751867] [Full Text: https://doi.org/10.1074/jbc.M110603200]
Vilkki, S., Launonen, V., Karhu, A., Sistonen, P., Vastrik, I., Aaltonen, L. A. Screening for microsatellite instability target genes in colorectal cancers. J. Med. Genet. 39: 785-789, 2002. [PubMed: 12414815] [Full Text: https://doi.org/10.1136/jmg.39.11.785]
Wong, A. K. C., Ormonde, P. A., Pero, R., Chen, Y., Lian, L., Salada, G., Berry, S., Lawrence, Q., Dayananth, P., Ha, P., Tavtigian, S. V., Teng, D. H.-F., Bartel, P. L. Characterization of a carboxy-terminal BRCA1 interacting protein. Oncogene 17: 2279-2285, 1998. [PubMed: 9811458] [Full Text: https://doi.org/10.1038/sj.onc.1202150]
Yu, X., Baer, R. Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. J. Biol. Chem. 275: 18541-18549, 2000. [PubMed: 10764811] [Full Text: https://doi.org/10.1074/jbc.M909494199]
Yu, X., Wu, L. C., Bowcock, A. M., Aronheim, A., Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273: 25388-25392, 1998. [PubMed: 9738006] [Full Text: https://doi.org/10.1074/jbc.273.39.25388]
Yun, M. H., Hiom, K. CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459: 460-463, 2009. [PubMed: 19357644] [Full Text: https://doi.org/10.1038/nature07955]