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Gene Review

RBBP8  -  retinoblastoma binding protein 8

Homo sapiens

Synonyms: COM1, CTIP, CtBP-interacting protein, CtIP, DNA endonuclease RBBP8, ...
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Disease relevance of RBBP8

  • Importantly, the life span of Ctip(+/-) heterozygotes was shortened by the development of multiple types of tumors, predominantly, large lymphomas [1].
  • However, depletion of Ctip failed to arrest Rb(-/-) mouse embryonic fibroblasts (MEF) or human osteosarcoma Saos-2 cells at G(1), suggesting that this arrest is RB dependent [1].
  • CtIP interacts with CtBP, a protein named for its ability to interact with the C-terminal sequences of adenovirus E1A [2].
  • The Ctip gene contains a mononucleotide (A9) repeat and one of the alleles is mutated at a high frequency in colon cancers with microsatellite instability [3].
  • The sensitivity of CTIP and CT without IP for detection of peritoneal metastases at all sites of involvement was 61% and 59%, respectively [4].

High impact information on RBBP8

  • We have shown that the BRCA1-binding domain of CtIP (amino-acid residues 133-369) is distal to the sites that are phosphorylated by ATM kinase (residues S664 and S745) [5].
  • Instead, ubiquitinated CtIP associates with chromatin following DNA damage and participates in G2/M checkpoint control [6].
  • This interaction depends on the p130 pocket domain, which is important for repression activity, as well as an LXCXE sequence within CtIP, a motif previously shown to mediate interactions of viral proteins with Rb [2].
  • The wild-type Ctip allele and protein remained detectable in these tumors, suggesting that haploid insufficiency of Ctip leads to tumorigenesis [1].
  • The corresponding Ctip(-/-) embryos died at embryonic day 4.0 (E4.0), and the blastocysts failed to enter S phase but accumulated in G(1), leading to a slightly elevated cell death [1].

Biological context of RBBP8


Anatomical context of RBBP8

  • A sequence based screen of a panel of 89 tumor cell line cDNAs for mutations in the CtIP coding region identified five missense variants [10].
  • A germ line truncation mutation, Y1853ter, that removes the last 11 amino acids from the carboxy-terminus of BRCA1, abolishes not only its transcriptional activation function, but also binding to CtIP [10].
  • CTIP and CT without IP had low sensitivity for detection of disease in the greater omentum (50% each) and small-bowel mesentery (38% and 59%, respectively), two areas that had the highest frequency of metastases [4].
  • Interestingly, TRB3 and CtIP co-localized to the nucleus in HeLa cells and exhibited a unique dot-like pattern [11].

Associations of RBBP8 with chemical compounds

  • Importantly, the side chain of Arg1775 in the cancer-associated BRCA1 mutation M1775R sterically clashes with the phenyl ring of CtIP Phe330, disrupting the BRCA1-CtIP interaction [12].

Physical interactions of RBBP8

  • CtIP has been proposed as a regulator of p21(Waf-1/Cip-1) gene transcription through a protein complex involving BRCA1 [13].
  • SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway [13].
  • Consistent with this expectation, we show that Ikaros can interact with a CtBP-interacting protein (CtIP), which has also been linked to a deacetylase-independent strategy of repression [14].

Regulatory relationships of RBBP8

  • Taken together, these data not only implicate CtIP as a critical player in cell cycle checkpoint control but also provide molecular mechanisms by which BRCA1 controls multiple cell cycle transitions after DNA damage [15].

Other interactions of RBBP8


Analytical, diagnostic and therapeutic context of RBBP8

  • Several hydrogen bonds and salt bridges that stabilize the BRCA1-BACH1 complex are missing in the BRCA1-CtIP interaction, offering a structural basis for the approximately 5-fold lower affinity of BRCA1 for CtIP compared to that of BACH1, as determined by isothermal titration calorimetry [12].


  1. Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Chen, P.L., Liu, F., Cai, S., Lin, X., Li, A., Chen, Y., Gu, B., Lee, E.Y., Lee, W.H. Mol. Cell. Biol. (2005) [Pubmed]
  2. A mechanism for Rb/p130-mediated transcription repression involving recruitment of the CtBP corepressor. Meloni, A.R., Smith, E.J., Nevins, J.R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. CtIP, a candidate tumor susceptibility gene is a team player with luminaries. Chinnadurai, G. Biochim. Biophys. Acta (2006) [Pubmed]
  4. Peritoneal carcinomatosis: preoperative CT with intraperitoneal contrast material. Nelson, R.C., Chezmar, J.L., Hoel, M.J., Buck, D.R., Sugarbaker, P.H. Radiology. (1992) [Pubmed]
  5. Effect of DNA damage on a BRCA1 complex. Wu-Baer, F., Baer, R. Nature (2001) [Pubmed]
  6. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Yu, X., Fu, S., Lai, M., Baer, R., Chen, J. Genes Dev. (2006) [Pubmed]
  7. Molecular cloning and characterization of a novel retinoblastoma-binding protein. Fusco, C., Reymond, A., Zervos, A.S. Genomics (1998) [Pubmed]
  8. Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. Yu, X., Baer, R. J. Biol. Chem. (2000) [Pubmed]
  9. Dimerization of CtIP, a BRCA1- and CtBP-interacting protein, is mediated by an N-terminal coiled-coil motif. Dubin, M.J., Stokes, P.H., Sum, E.Y., Williams, R.S., Valova, V.A., Robinson, P.J., Lindeman, G.J., Glover, J.N., Visvader, J.E., Matthews, J.M. J. Biol. Chem. (2004) [Pubmed]
  10. Characterization of a carboxy-terminal BRCA1 interacting protein. Wong, A.K., 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., Bartel, P.L. Oncogene (1998) [Pubmed]
  11. TRB3 interacts with CtIP and is overexpressed in certain cancers. Xu, J., Lv, S., Qin, Y., Shu, F., Xu, Y., Chen, J., Xu, B.E., Sun, X., Wu, J. Biochim. Biophys. Acta (2007) [Pubmed]
  12. Structural basis for cell cycle checkpoint control by the BRCA1-CtIP complex. Varma, A.K., Brown, R.S., Birrane, G., Ladias, J.A. Biochemistry (2005) [Pubmed]
  13. SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway. Germani, A., Prabel, A., Mourah, S., Podgorniak, M.P., Di Carlo, A., Ehrlich, R., Gisselbrecht, S., Varin-Blank, N., Calvo, F., Bruzzoni-Giovanelli, H. Oncogene (2003) [Pubmed]
  14. Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression. Koipally, J., Georgopoulos, K. J. Biol. Chem. (2002) [Pubmed]
  15. DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Yu, X., Chen, J. Mol. Cell. Biol. (2004) [Pubmed]
  16. The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumor suppressor BRCA1 and inhibits BRCA1 activity. Sum, E.Y., Peng, B., Yu, X., Chen, J., Byrne, J., Lindeman, G.J., Visvader, J.E. J. Biol. Chem. (2002) [Pubmed]
  17. Mutational analysis of the LMO4 gene, encoding a BRCA1-interacting protein, in breast carcinomas. Sutherland, K.D., Visvader, J.E., Choong, D.Y., Sum, E.Y., Lindeman, G.J., Campbell, I.G. Int. J. Cancer (2003) [Pubmed]
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