ID:COM1_HUMAN DESCRIPTION: RecName: Full=DNA endonuclease RBBP8; EC=3.1.-.-; AltName: Full=CtBP-interacting protein; Short=CtIP; AltName: Full=Retinoblastoma-binding protein 8; Short=RBBP-8; AltName: Full=Retinoblastoma-interacting protein and myosin-like; Short=RIM; AltName: Full=Sporulation in the absence of SPO11 protein 2 homolog; Short=SAE2; FUNCTION: Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in processing meiotic and mitotic double-strand breaks (DSBs) by ensuring both resection and intrachromosomal association of the broken ends. Functions downstream of the MRN complex and ATM, promotes ATR activation and its recruitment to DSBs in the S/G2 phase facilitating the generation of ssDNA. Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage. Promotes microhomology-mediated alternative end joining (A-NHEJ) during class-switch recombination and plays an essential role in chromosomal translocations. SUBUNIT: Homodimer; dimerizes via the coiled coil domain. Interacts (via the PXDLS motif) with CTBP1; the interaction is disrupted via binding of the adenovirus E1A to CTBP1. Component of the BRCA1-RBBBP8 complex. Interacts (the Ser-327 phosphorylated form) with BRCA1 (via the C-terminal BRCA1 domains): the interaction occurs in the G2 phase, ubiquitinates RBBP8 and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage. Interacts with RB1. Interacts with the MRN complex. Interacts directly with MRE11A; the interaction is required for efficient homologous recombination (HR) and regulation of the MRN complex. Interacts directly with RAD50. Interacts directly with NBN. Interacts with SIRT6; the interaction deacetylates RBBP8 upon DNA damage. Interacts with LM04 (via the LIM zinc-binding 1 domain). INTERACTION: P38398:BRCA1; NbExp=9; IntAct=EBI-745715, EBI-349905; SUBCELLULAR LOCATION: Nucleus. Note=Associates with sites of DNA damage in S/G2 phase. Ubiquitinated RBBP8 binds to chromatin following DNA damage. INDUCTION: Levels increase dramatically as dividing cells traverse the G1/S boubdary. Down-regulated in tamoxifen-resistant breast cancer cells. DOMAIN: The PXDLS motif binds to a cleft in CtBP proteins. DOMAIN: The damage-recruitment motif is required for DNA binding and translocation to sites of DNA damage. PTM: Acetylated. Deacetylation by SIRT6 upon DNA damage promotes DNA end resection. PTM: Phosphorylated upon DNA damage, probably by ATM or ATR. Hyperphosphorylation upon ionizing radiation results in dissociation from BRCA1. Phosphorylation at Thr-847 by CDK1 is essential for the recruitment to DNA and the DNA repair function. Phosphorylated on Ser-327 as cells enter G2 phase. This phosphorylation is required for binding BRCA1 and for the G2/M DNA damage transition checkpoint control. PTM: Ubiquitinated. Ubiquitination at multiple sites by BRCA1 (via its N-terminal RING domain) does not lead to its proteosomal degradation but instead the ubiquitinated RBBP8 binds to chromatin following DNA damage and may play a role in G2/M checkpoint control. DISEASE: Defects in RBBP8 are a cause of Seckel syndrome type 2 (SCKL2) [MIM:606744]. SCKL2 is a rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. DISEASE: Defects in RBBP8 are a cause of Jawad disease (JWDS) [MIM:251255]. JWDS is a syndrome characterized by congenital microcephaly, moderately severe mental retardation, and symmetrical digital anomalies. Digital malformations of variable degree inclued hallux valgus, syndactyly of toes 4 and 5, short fifth fingers, single flexion crease of fifth fingers, polydactyly and synpolydactyly. DISEASE: Note=Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk. Exhibits sensitivity to tamoxifen in certain breast cancer cell lines. SIMILARITY: Belongs to the COM1/SAE2/CtIP family. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org//Genes/RBBP8ID42066ch18q11.html";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q99708
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000014 single-stranded DNA endodeoxyribonuclease activity GO:0001103 RNA polymerase II repressing transcription factor binding GO:0001106 RNA polymerase II transcription corepressor activity GO:0003677 DNA binding GO:0003684 damaged DNA binding GO:0004518 nuclease activity GO:0004519 endonuclease activity GO:0005515 protein binding GO:0016787 hydrolase activity GO:0042802 identical protein binding
Biological Process: GO:0000082 G1/S transition of mitotic cell cycle GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0000724 double-strand break repair via homologous recombination GO:0000729 DNA double-strand break processing GO:0001835 blastocyst hatching GO:0006260 DNA replication GO:0006281 DNA repair GO:0006289 nucleotide-excision repair GO:0006357 regulation of transcription from RNA polymerase II promoter GO:0006974 cellular response to DNA damage stimulus GO:0007049 cell cycle GO:0010792 DNA double-strand break processing involved in repair via single-strand annealing GO:0031572 G2 DNA damage checkpoint GO:0032355 response to estradiol GO:0051301 cell division GO:0051321 meiotic cell cycle GO:0070317 negative regulation of G0 to G1 transition GO:0090305 nucleic acid phosphodiester bond hydrolysis GO:1903507 negative regulation of nucleic acid-templated transcription
LP896090 - Sequence 954 from Patent EP3253886. U72066 - Homo sapiens CtBP interacting protein CtIP (CtIP) mRNA, complete cds. AK292481 - Homo sapiens cDNA FLJ75801 complete cds, highly similar to Homo sapiens retinoblastoma binding protein 8 (RBBP8), transcript variant 1, mRNA. AF043431 - Homo sapiens retinoblastoma-interacting protein (RBBP8) mRNA, complete cds. BX648221 - Homo sapiens mRNA; cDNA DKFZp686E1976 (from clone DKFZp686E1976). BC030590 - Homo sapiens retinoblastoma binding protein 8, mRNA (cDNA clone MGC:26464 IMAGE:4830693), complete cds. AB590310 - Synthetic construct DNA, clone: pFN21AB8544, Homo sapiens RBBP8 gene for retinoblastoma binding protein 8, without stop codon, in Flexi system. DQ894119 - Synthetic construct Homo sapiens clone IMAGE:100008579; FLH167941.01L; RZPDo839H0789D retinoblastoma binding protein 8 (RBBP8) gene, encodes complete protein. KJ901696 - Synthetic construct Homo sapiens clone ccsbBroadEn_11090 RBBP8 gene, encodes complete protein. DQ890956 - Synthetic construct clone IMAGE:100003586; FLH167944.01X; RZPDo839H0790D retinoblastoma binding protein 8 (RBBP8) gene, encodes complete protein. HZ409545 - JP 2015528002-A/2142: CHIRAL CONTROL. HZ459519 - WO 2015182781-A/222: Kit or device and method for detecting pancreatic cancer. HZ460224 - WO 2015190542-A/230: Kit or device and method for detecting biliary tract cancer. HZ460737 - WO 2015190584-A/234: Kit or device and method for detecting prostate cancer. HZ461499 - WO 2015190586-A/312: Kit and method for detecting colon cancer. HZ462167 - WO 2015190591-A/322: Kit and method for detecting breast cancer. HZ463204 - WO 2015194535-A/298: Kit and method for detecting stomach cancer. HZ464607 - WO 2015194615-A/425: Kit or device and method for detecting hepatic cancer. HZ465257 - WO 2015194627-A/310: Kit and method for detecting esophageal cancer. LG052879 - KR 1020150036642-A/2145: CHIRAL CONTROL. LY480959 - KR 1020170010856-A/222: PANCREATIC CANCER DETECTION KIT, DEVICE, AND DETECTION METHOD. LY495851 - KR 1020170015509-A/230: DETECTION KIT OR DEVICE AND DETECTION METHOD FOR BILIARY TRACT CANCER. LY496440 - KR 1020170018406-A/310: ESOPHAGEAL CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY497142 - KR 1020170016485-A/312: COLORECTAL CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY498508 - KR 1020170018411-A/425: LIVER CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY499170 - KR 1020170018412-A/322: BREAST CANCER DETECTION KIT OR DEVICE, AND METHOD FOR DETECTING BREAST CANCER. LY500017 - KR 1020170019425-A/298: STOMACH CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY500610 - KR 1020170016490-A/234: PROSTATE CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LZ238729 - WO 2017171048-A/390: Kit, device and method for detecting early pancreatic cancer or precancerous lesion of pancreas. MS869016 - Sequence 230 from Patent EP3156500. MS869529 - Sequence 234 from Patent EP3156483. MS880485 - Sequence 322 from Patent EP3156498. MS884329 - Sequence 312 from Patent EP3156499. MS885136 - Sequence 298 from Patent EP3156503. MS994448 - Sequence 310 from Patent EP3159406. HZ459613 - WO 2015182781-A/316: Kit or device and method for detecting pancreatic cancer. HZ460374 - WO 2015190542-A/380: Kit or device and method for detecting biliary tract cancer. HZ460933 - WO 2015190584-A/430: Kit or device and method for detecting prostate cancer. HZ461711 - WO 2015190586-A/524: Kit and method for detecting colon cancer. HZ462444 - WO 2015190591-A/599: Kit and method for detecting breast cancer. HZ463405 - WO 2015194535-A/499: Kit and method for detecting stomach cancer. HZ464872 - WO 2015194615-A/690: Kit or device and method for detecting hepatic cancer. HZ465465 - WO 2015194627-A/518: Kit and method for detecting esophageal cancer. LY481053 - KR 1020170010856-A/316: PANCREATIC CANCER DETECTION KIT, DEVICE, AND DETECTION METHOD. LY496001 - KR 1020170015509-A/380: DETECTION KIT OR DEVICE AND DETECTION METHOD FOR BILIARY TRACT CANCER. LY496648 - KR 1020170018406-A/518: ESOPHAGEAL CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY497354 - KR 1020170016485-A/524: COLORECTAL CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY498773 - KR 1020170018411-A/690: LIVER CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY499447 - KR 1020170018412-A/599: BREAST CANCER DETECTION KIT OR DEVICE, AND METHOD FOR DETECTING BREAST CANCER. LY500218 - KR 1020170019425-A/499: STOMACH CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY500806 - KR 1020170016490-A/430: PROSTATE CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LZ238998 - WO 2017171048-A/659: Kit, device and method for detecting early pancreatic cancer or precancerous lesion of pancreas. MS869166 - Sequence 380 from Patent EP3156500. MS869725 - Sequence 430 from Patent EP3156483. MS880762 - Sequence 599 from Patent EP3156498. MS884541 - Sequence 524 from Patent EP3156499. MS885337 - Sequence 499 from Patent EP3156503. MS994656 - Sequence 518 from Patent EP3159406. FR773033 - Homo sapiens microRNA hsa-miR-4741-3p. HW798993 - WO 2014192907-A/99: Method for detecting miRNA used for differentiating disorders causing motor neuropathy. HW906944 - WO 2015037656-A/159: Autophagy-regulating microRNA. HZ459396 - WO 2015182781-A/99: Kit or device and method for detecting pancreatic cancer. HZ460074 - WO 2015190542-A/80: Kit or device and method for detecting biliary tract cancer. HZ460551 - WO 2015190584-A/48: Kit or device and method for detecting prostate cancer. HZ461306 - WO 2015190586-A/119: Kit and method for detecting colon cancer. HZ461897 - WO 2015190591-A/52: Kit and method for detecting breast cancer. HZ463005 - WO 2015194535-A/99: Kit and method for detecting stomach cancer. HZ464389 - WO 2015194615-A/207: Kit or device and method for detecting hepatic cancer. HZ465042 - WO 2015194627-A/95: Kit and method for detecting esophageal cancer. HZ481909 - JP 2015535430-A/2415: TERMINALLY MODIFIED RNA. HZ791840 - JP 2016504050-A/3585: SIGNAL-SENSOR POLYNUCLEOTIDES FOR THE ALTERATION OF CELLULAR PHENOTYPES. JC514572 - Sequence 4825 from Patent WO2014113089. LF160746 - JP 2016513950-A/812: Oligomers with improved off-target profile. LF632705 - WO 2016117582-A/134: miRNA biomarkers for mental disorders. LP951829 - Sequence 335 from Patent WO2017157650. LQ072160 - Sequence 2484 from Patent EP2964234. LQ724942 - Sequence 575 from Patent WO2018096084. LY480836 - KR 1020170010856-A/99: PANCREATIC CANCER DETECTION KIT, DEVICE, AND DETECTION METHOD. LY495701 - KR 1020170015509-A/80: DETECTION KIT OR DEVICE AND DETECTION METHOD FOR BILIARY TRACT CANCER. LY496225 - KR 1020170018406-A/95: ESOPHAGEAL CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY496949 - KR 1020170016485-A/119: COLORECTAL CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY498290 - KR 1020170018411-A/207: LIVER CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY498900 - KR 1020170018412-A/52: BREAST CANCER DETECTION KIT OR DEVICE, AND METHOD FOR DETECTING BREAST CANCER. LY499818 - KR 1020170019425-A/99: STOMACH CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LY500424 - KR 1020170016490-A/48: PROSTATE CANCER DETECTION KIT OR DEVICE, AND DETECTION METHOD. LZ238472 - WO 2017171048-A/133: Kit, device and method for detecting early pancreatic cancer or precancerous lesion of pancreas. MS868866 - Sequence 80 from Patent EP3156500. MS869343 - Sequence 48 from Patent EP3156483. MS880215 - Sequence 52 from Patent EP3156498. MS884136 - Sequence 119 from Patent EP3156499. MS884937 - Sequence 99 from Patent EP3156503. MS994233 - Sequence 95 from Patent EP3159406. BC001170 - Homo sapiens, Similar to retinoblastoma-binding protein 8, clone IMAGE:3357638, mRNA. JD487087 - Sequence 468111 from Patent EP1572962. CU688926 - Synthetic construct Homo sapiens gateway clone IMAGE:100017833 5' read RBBP8 mRNA. MA645661 - JP 2017113010-A/3585: SIGNAL-SENSOR POLYNUCLEOTIDES FOR THE ALTERATION OF CELLULAR PHENOTYPES. MA733545 - JP 2017140048-A/2415: TERMINALLY MODIFIED RNA. MA406086 - WO 2018155427-A/860: A probe with reduced false positive binding, a method to desing the probe, and the use thereof. MA802714 - JP 2018183181-A/3585: SIGNAL-SENSOR POLYNUCLEOTIDES FOR THE ALTERATION OF CELLULAR PHENOTYPES. LY616493 - KR 1020180129785-A/390: KIT OR DEVICE FOR DETECTING EARLY STAGE PANCREATIC CANCER OR PANCREATIC CANCER PRECURSOR LESIONS AND DETECTION METHOD THEREFOR. LY616762 - KR 1020180129785-A/659: KIT OR DEVICE FOR DETECTING EARLY STAGE PANCREATIC CANCER OR PANCREATIC CANCER PRECURSOR LESIONS AND DETECTION METHOD THEREFOR. LY616236 - KR 1020180129785-A/133: KIT OR DEVICE FOR DETECTING EARLY STAGE PANCREATIC CANCER OR PANCREATIC CANCER PRECURSOR LESIONS AND DETECTION METHOD THEREFOR. MB407355 - WO 2019159884-A/845: Kit, device, and method for detection of dementia. MB406569 - WO 2019159884-A/59: Kit, device, and method for detection of dementia. MB406965 - WO 2019159884-A/455: Kit, device, and method for detection of dementia. MB472967 - WO 2019208671-A/366: Kit or device and method for detecting bladder cancer. MB473193 - WO 2019208671-A/592: Kit or device and method for detecting bladder cancer. MB472732 - WO 2019208671-A/131: Kit or device and method for detecting bladder cancer. JD473260 - Sequence 454284 from Patent EP1572962. JD281591 - Sequence 262615 from Patent EP1572962. JD211081 - Sequence 192105 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_atmPathway - ATM Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein Q99708 (Reactome details) participates in the following event(s):
R-HSA-5684081 MRN complex binds CDK2 and RBBP8 R-HSA-5687465 MRN complex binds RBBP8 R-HSA-5685953 SIRT6 deacetylates RBBP8 R-HSA-5687675 LIG3 ligates remaining SSBs in MMEJ R-HSA-5686410 BLM mediates dissolution of double Holliday junction R-HSA-5686657 ERCC1:XPF cleaves flaps generated by SSA R-HSA-5693589 D-loop dissociation and strand annealing R-HSA-5684096 CDK2 phosphorylates RBBP8 R-HSA-5687484 PARP1 or PARP2, FEN1 and POLQ are recruited to MMEJ site R-HSA-5687464 MRN and RBBP8 resect DNA DSBs in MMEJ R-HSA-5687673 MRN recruits LIG3:XRCC1 to MMEJ sites R-HSA-5687664 FEN1 cleaves displaced ssDNA flaps during MMEJ R-HSA-5684140 ATM phosphorylates RBBP8 R-HSA-5684108 BRCA1 binds phosphorylated RBBP8 R-HSA-5687640 POLQ extends annealed 3'-ssDNA overhangs in MMEJ R-HSA-5687653 PARP1,PARP2 dimers bound to MMEJ sites autoPARylate R-HSA-5693608 Initial resection of double-strand break ends R-HSA-5693542 Association of RPA complexes with ssDNA at resected DNA DSBs R-HSA-5685994 Long-range resection of DNA DSBs by EXO1 or DNA2 R-HSA-5685341 BCDX2 complex stabilizes RAD51 filament R-HSA-5693561 RAD51 binds BRCA2 at resected DNA DSBs R-HSA-5685985 EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment R-HSA-5684875 Binding of ATR:ATRIP to RPA at resected DNA DSBs R-HSA-5693620 D-loop formation mediated by PALB2, BRCA2 and RAD51 R-HSA-5685838 CX3 complex binds D-loop structures R-HSA-5685011 ATR activation at DNA DSBs R-HSA-5684887 Activation of CHEK1 at resected DNA DSBs R-HSA-5684882 CHEK1 is recruited to resected DNA DSBs R-HSA-5693580 Association of RAD52 with the RPA complex at resected DNA DSBs R-HSA-5685156 ATR phosphorylates RPA2 R-HSA-5693593 D-loop extension by DNA polymerases R-HSA-5693584 Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2) R-HSA-5686440 MUS81:EME1,EME2 cleaves D-loop R-HSA-5693564 Association of RAD51 with RAD52:DNA double-strand break ends R-HSA-6799332 ATR phosphorylates TP53 R-HSA-5686642 RAD52 promotes single strand annealing at resected DNA DSBs R-HSA-8953750 Transcriptional Regulation by E2F6 R-HSA-5693607 Processing of DNA double-strand break ends R-HSA-5685939 HDR through MMEJ (alt-NHEJ) R-HSA-212436 Generic Transcription Pathway R-HSA-5693568 Resolution of D-loop Structures through Holliday Junction Intermediates R-HSA-5685938 HDR through Single Strand Annealing (SSA) R-HSA-5693554 Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) R-HSA-912446 Meiotic recombination R-HSA-5693567 HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA) R-HSA-5693538 Homology Directed Repair R-HSA-73857 RNA Polymerase II Transcription R-HSA-5693537 Resolution of D-Loop Structures R-HSA-1500620 Meiosis R-HSA-5693532 DNA Double-Strand Break Repair R-HSA-74160 Gene expression (Transcription) R-HSA-5693616 Presynaptic phase of homologous DNA pairing and strand exchange R-HSA-5685942 HDR through Homologous Recombination (HRR) R-HSA-1474165 Reproduction R-HSA-1640170 Cell Cycle R-HSA-73894 DNA Repair R-HSA-5693579 Homologous DNA Pairing and Strand Exchange R-HSA-69473 G2/M DNA damage checkpoint R-HSA-6804756 Regulation of TP53 Activity through Phosphorylation R-HSA-69481 G2/M Checkpoints R-HSA-5633007 Regulation of TP53 Activity R-HSA-69620 Cell Cycle Checkpoints R-HSA-3700989 Transcriptional Regulation by TP53
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
