RBBP8 (retinoblastoma binding protein 8)

2008-05-01   Govindaswamy Chinnadurai , Thirugnana Subramanian , Selvamani Vijayalingam 

Institute for Molecular, Virology, Saint Louis University School of Medicine, Doisy Research Center, 1100 South Grand Blvd, St. Louis, Missouri 63104, USA

Identity

HGNC
LOCATION
18q11.2
LOCUSID
ALIAS
COM1,CTIP,JWDS,RIM,SAE2,SCKL2
FUSION GENES

DNA/RNA

Atlas Image

Description

The gene encompasses 93.155 Kb of DNA.

Transcription

3279 bp mRNA.

Proteins

Atlas Image
Domain structure of hCtIP. All known CtIP proteins contain a highly conserved CtBP-binding motif, two CXXC motifs and a phosphorylation site that corresponds to Ser327 in hCtIP. The Rb-binding motif is conserved only in mammalian CtIP. The N-terminal and C-terminal regions of all the CtIP homologs show high degrees of conservation. The ATM target site that corresponds to Ser664 is not conserved in CtIP of certain species (e.g., mouse and chicken). The A9 repeat, a tumor-specific nucleotide polymorphism (G2115A) and a nucleotide polymorphism (G1766A) resulting in an amino acid substitution (K589H) observed in tumor and normal cells are indicated. The region between amino acid positions 45 to 160 is a coiled-coil. A C-terminal region conserved between CtIPs and the plant (Arabidopsis thaliana) gamma response 1 (AtGR1) protein is also indicated (light blue).

Description

897 a.a. polypeptide.

Expression

Widely expressed in various human tissues - thymus and testis appear to express the highest levels.

Localisation

Predominantly localized in the nucleus; contains 4 potential nuclear localization signals and two leucine zipper motifs, a Rb binding domain, a CtBP binding motif, a coiled-coil domain, two CXXC motifs similar to the Zn-hook motif of Rad50.

Function

Potential modulator of BRCA1 in transcriptional regulation, DNA repair and cell cycle checkpoint control.
Family: ezrin/radixin/myosin family
Category: regulatory, transcription factor, antioncogene
Interaction: binds to Rb, CtBP, BRCA1, LMO4, SIAH1, Ikaros, MRE11 complex.

Homology

Homolog to C.elegans r05d3.4, fission yeast Ctp1. CtIP is conserved among vertebrates. A C-terminal domain of CtIP is homologous to plant gamma response 1(AtGR1) protein of Arabidopsis thaliana.
Variant: CtIP splice variant (Genebank Accession # NP_976037) with 867 a.a. is identical to CtIP except the C-terminal region (a.a. 786-867).

Mutations

Germinal

Knockout mice experiment has shown that inactivation of both CtIP alleles resulted in early embryonic lethality at stage E4. However the heterozygous CtIP+/- mice were viable with reduced life span due to development of multiple tumors.

Somatic

A number of human tumor cell lines derived from various tissues did not detect any homozygous deletion within the CtIP gene. However, some missense and silent mutations have been reported.

Implicated in

Entity name
Tumors
Disease
Recent studies with mutant mice have raised the possibility that Ctip might be a tumor suppressor gene. Inactivation of both Ctip alleles results in early embryonic lethality at stage E4. However, the heterozygous Ctip+/- mice are viable, but the life span is reduced compared to Ctip+/+ animals due to the development of multiple tumors. Among the types of tumors observed in Ctip+/- animals, B and T cell lymphomas (B-NHL and T-NHL) are most prevalent. Enhanced lymphoid specificity of tumorigenesis might reflect the fact that these tissues are active sites of DNA repair and CtIP insufficiency might contribute to lymphoma development due to potential defects in DNA repair.
Oncogenesis
Since CtIP seems to be very important for the activities of tumor suppressors such as BRCA1, pRb family and Ikaros family, CtIP may be a tumor suppressor protein.

Bibliography

Pubmed IDLast YearTitleAuthors
158314592005Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency.Chen PL et al
162490562006CtIP, a candidate tumor susceptibility gene is a team player with luminaries.Chinnadurai G et al
97212051998Molecular cloning and characterization of a novel retinoblastoma-binding protein.Fusco C et al
101962241999Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage.Li S et al
179367102007Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination.Limbo O et al
179657292007Human CtIP promotes DNA end resection.Sartori AA et al
95358251998Interaction 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.Schaeper U et al
98114581998Characterization of a carboxy-terminal BRCA1 interacting protein.Wong AK et al
107648112000Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor.Yu X et al
97380061998The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression.Yu X et al

Other Information

Locus ID:

NCBI: 5932
MIM: 604124
HGNC: 9891
Ensembl: ENSG00000101773

Variants:

dbSNP: 5932
ClinVar: 5932
TCGA: ENSG00000101773
COSMIC: RBBP8

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000101773ENST00000327155Q99708
ENSG00000101773ENST00000327155A0A024RC34
ENSG00000101773ENST00000360790I6L8A6
ENSG00000101773ENST00000399721F6Q6H0
ENSG00000101773ENST00000399722Q99708
ENSG00000101773ENST00000399722A0A024RC34
ENSG00000101773ENST00000399725Q99708
ENSG00000101773ENST00000577445J3QL00
ENSG00000101773ENST00000577588J3QRM0
ENSG00000101773ENST00000579124J3KSA4
ENSG00000101773ENST00000581687J3QLH2
ENSG00000101773ENST00000581819J3QL93
ENSG00000101773ENST00000582354J3QLW6
ENSG00000101773ENST00000583057J3QSH7
ENSG00000101773ENST00000583700A0A140TA82
ENSG00000101773ENST00000585177V9GZ40

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Homologous recombinationKEGGhsa03440
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
MeiosisREACTOMER-HSA-1500620
Meiotic recombinationREACTOMER-HSA-912446
DNA RepairREACTOMER-HSA-73894
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
Resolution of D-Loop StructuresREACTOMER-HSA-5693537
Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
HDR through MMEJ (alt-NHEJ)REACTOMER-HSA-5685939
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
179657292007Human CtIP promotes DNA end resection.606
233333062013A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice.343
193576442009CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle.235
192021912009Human CtIP mediates cell cycle control of DNA end resection and double strand break repair.204
181716702008Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair.190
196336682009Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells.161
200644622009CtIP links DNA double-strand break sensing to resection.114
248376762014Catalytic and noncatalytic roles of the CtIP endonuclease in double-strand break end resection.74
234686392013The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair.73
162878522005RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes.69

Citation

Govindaswamy Chinnadurai ; Thirugnana Subramanian ; Selvamani Vijayalingam

RBBP8 (retinoblastoma binding protein 8)

Atlas Genet Cytogenet Oncol Haematol. 2008-05-01

Online version: http://atlasgeneticsoncology.org/gene/42066/rbbp8