RBBP8

The protein encoded by this gene is a ubiquitously expressed nuclear protein. It is found among several proteins that bind directly to retinoblastoma protein, which regulates cell proliferation. This protein complexes with transcriptional co-repressor CTBP. It is also associated with BRCA1 and is thought to modulate the functions of BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control. It is suggested that this gene may itself be a tumor suppressor acting in the same pathway as BRCA1. Three transcript variants encoding two different isoforms have been found for this gene. More transcript variants exist, but their full-length natures have not been determined. [provided by RefSeq, Jul 2008]

RB Binding Protein 8, Endonuclease

Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in DNA-end resection, the first step of double-strand break (DSB) repair through the homologous recombination (HR) pathway (PubMed:17965729, PubMed:19202191, PubMed:19759395, PubMed:20064462, PubMed:26721387).
HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse (PubMed:17965729, PubMed:19202191).
Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end-joining (NHEJ) (PubMed:19202191).
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 (PubMed:16581787, PubMed:17965729, PubMed:19759395, PubMed:20064462).
Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage (PubMed:15485915, PubMed:16818604).
During immunoglobulin heavy chain class-switch recombination, promotes microhomology-mediated alternative end joining (A-NHEJ) and plays an essential role in chromosomal translocations (By similarity).

Biological Process blastocyst hatchingIEA:Ensembl
Biological Process cell divisionIEA:UniProtKB-KW
Biological Process DNA double-strand break processing involved in repair via single-strand annealingManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process DNA repairManual Assertion Based On ExperimentTAS:ProtInc
Biological Process DNA strand resection involved in replication fork processing1 PublicationIC:ComplexPortal
Biological Process double-strand break repair via homologous recombinationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process G1/S transition of mitotic cell cycleIEA:Ensembl
Biological Process homologous recombination1 PublicationIC:ComplexPortal
Biological Process meiotic cell cycleIEA:UniProtKB-KW
Biological Process mitotic G2/M transition checkpoint1 PublicationIC:ComplexPortal
Biological Process positive regulation of double-strand break repair via homologous recombinationManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentTAS:ProtInc

Nucleus
Chromosome
Associates with sites of DNA damage in S/G2 phase (PubMed:10764811, PubMed:25349192).
Ubiquitinated RBBP8 binds to chromatin following DNA damage (PubMed:16818604).

Seckel syndrome 2 (SCKL2):
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 intellectual disability.
Jawad syndrome (JWDS):
A syndrome characterized by congenital microcephaly, moderately severe intellectual disability, and symmetrical digital anomalies. Digital malformations of variable degree include hallux valgus, syndactyly of toes 4 and 5, short fifth fingers, single flexion crease of fifth fingers, polydactyly and synpolydactyly.

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. Phosphorylation at Thr-315, probably catalyzed by CDK2, is required for PIN1-binding, while phosphorylation at Ser-276 serves as a PIN1 isomerization site. Phosphorylation at Thr-315 is cell-cycle dependent. It steadily increases during S phase, peaks at late S/G2 phase, and drops at G1 (PubMed:23623683).
Ubiquitinated (PubMed:14654780, PubMed:16818604, PubMed:27561354).
Ubiquitination at multiple sites by BRCA1 (via its N-terminal RING domain) does not lead to its proteasomal degradation but instead the ubiquitinated RBBP8 binds to chromatin following DNA damage and may play a role in G2/M checkpoint control (PubMed:16818604).
Ubiquitinated by RNF138 at its N-terminus (PubMed:26502057).
Ubiquitinated through 'Lys-48' by the E3 CUL3-KLHL15 complex; this modification leads to proteasomal degradation (PubMed:27561354).
Ubiquitinated by the E3 FZR1/APC/C complex; this modification leads to proteasomal degradation (PubMed:25349192).