UniProt functional annotation for Q99708



	UniProt functional annotation for Q99708

UniProt code: Q99708.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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). 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). {ECO:0000250|UniProtKB:Q80YR6, ECO:0000269|PubMed:15485915, ECO:0000269|PubMed:16581787, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:17965729, ECO:0000269|PubMed:19202191, ECO:0000269|PubMed:19759395, ECO:0000269|PubMed:20064462}.

Subunit: Homodimer; dimerizes via the coiled coil domain (PubMed:15084581). Interacts (via the PXDLS motif) with CTBP1; the interaction is disrupted via binding of the adenovirus E1A to CTBP1 (PubMed:9535825). Component of the BRCA1-RBBP8 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 (PubMed:10764811, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:23623683). Interacts with RB1 (PubMed:9721205). Interacts with the MRN complex. Interacts directly with MRE11; the interaction is required for efficient homologous recombination (HR) and regulation of the MRN complex (PubMed:19759395, PubMed:23623683). Interacts directly with RAD50 (PubMed:19759395). Interacts directly with NBN (PubMed:19759395). Interacts with LM04 (via the LIM zinc- binding 1 domain) (PubMed:11751867). Interacts with SIAH1 (PubMed:14654780). Interacts with RNF138 (PubMed:26502057). Interacts with EXD2 (PubMed:26807646). Interacts with CUL3 and KLHL15; this interaction leads to RBBP8 proteasomal degradation (PubMed:27561354). Directly interacts with PIN1; this interaction depends upon RBBP8 phosphorylation, predominantly at Thr-315 (PubMed:23623683). Interacts with FZR1; this interaction leads to APC/C-mediated RBBP8 proteasomal degradation (PubMed:25349192). Interacts with AUNIP; leading to recruit RBBP8 to sites of DNA damage (PubMed:29042561, PubMed:10764811, PubMed:11751867, PubMed:14654780, PubMed:15084581, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:19759395, PubMed:23623683, PubMed:25349192, PubMed:26502057, PubMed:26807646, PubMed:27561354, PubMed:9535825, PubMed:9721205). Interacts with SAMHD1 (PubMed:28834754). {ECO:0000269|PubMed:10764811, ECO:0000269|PubMed:11751867, ECO:0000269|PubMed:14654780, ECO:0000269|PubMed:15084581, ECO:0000269|PubMed:15485915, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:17965729, ECO:0000269|PubMed:19759395, ECO:0000269|PubMed:23623683, ECO:0000269|PubMed:25349192, ECO:0000269|PubMed:26502057, ECO:0000269|PubMed:26807646, ECO:0000269|PubMed:27561354, ECO:0000269|PubMed:28834754, ECO:0000269|PubMed:29042561, ECO:0000269|PubMed:9535825, ECO:0000269|PubMed:9721205}.

Subcellular location: Nucleus {ECO:0000269|PubMed:10764811, ECO:0000269|PubMed:17965729, ECO:0000269|PubMed:23623683}. Chromosome {ECO:0000269|PubMed:10764811, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:29042561}. Note=Associates with sites of DNA damage in S/G2 phase (PubMed:10764811, PubMed:25349192). Ubiquitinated RBBP8 binds to chromatin following DNA damage (PubMed:16818604). {ECO:0000269|PubMed:10764811, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:25349192}.

Tissue specificity: Expressed in ER-positive breast cancer lines, but tends to be down-regulated ER-negative cells (at protein level). {ECO:0000269|PubMed:18171986}.

Induction: Expression is cell-cycle regulated. Levels increase as dividing cells traverse the G1/S boundary (PubMed:18171986). The protein is degraded by the proteasome pathway during mitotic exit. Also degraded in response to DNA damage in G2 cells; this degradation is mediated by the E3 FZR1/APC/C complex (PubMed:25349192). {ECO:0000269|PubMed:18171986, ECO:0000269|PubMed:25349192}.

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: 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). {ECO:0000269|PubMed:10910365, ECO:0000269|PubMed:15485915, ECO:0000269|PubMed:17965729, ECO:0000269|PubMed:19202191, ECO:0000269|PubMed:23623683}.

Ptm: 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). {ECO:0000269|PubMed:14654780, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:25349192, ECO:0000269|PubMed:26502057, ECO:0000269|PubMed:27561354}.

Disease: Seckel syndrome 2 (SCKL2) [MIM:606744]: 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. {ECO:0000269|PubMed:21998596, ECO:0000269|PubMed:24389050}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Jawad syndrome (JWDS) [MIM:251255]: A syndrome characterized by congenital microcephaly, moderately severe mental retardation, 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. {ECO:0000269|PubMed:21998596}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Note=Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk (PubMed:21799032). Associated with sensitivity to tamoxifen in certain breast cancer cell lines (PubMed:18171986). {ECO:0000269|PubMed:18171986, ECO:0000269|PubMed:21799032}.

Similarity: Belongs to the COM1/SAE2/CtIP family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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). 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). {ECO:0000250\|UniProtKB:Q80YR6, ECO:0000269\|PubMed:15485915, ECO:0000269\|PubMed:16581787, ECO:0000269\|PubMed:16818604, ECO:0000269\|PubMed:17965729, ECO:0000269\|PubMed:19202191, ECO:0000269\|PubMed:19759395, ECO:0000269\|PubMed:20064462}.


Subunit:		Homodimer; dimerizes via the coiled coil domain (PubMed:15084581). Interacts (via the PXDLS motif) with CTBP1; the interaction is disrupted via binding of the adenovirus E1A to CTBP1 (PubMed:9535825). Component of the BRCA1-RBBP8 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 (PubMed:10764811, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:23623683). Interacts with RB1 (PubMed:9721205). Interacts with the MRN complex. Interacts directly with MRE11; the interaction is required for efficient homologous recombination (HR) and regulation of the MRN complex (PubMed:19759395, PubMed:23623683). Interacts directly with RAD50 (PubMed:19759395). Interacts directly with NBN (PubMed:19759395). Interacts with LM04 (via the LIM zinc- binding 1 domain) (PubMed:11751867). Interacts with SIAH1 (PubMed:14654780). Interacts with RNF138 (PubMed:26502057). Interacts with EXD2 (PubMed:26807646). Interacts with CUL3 and KLHL15; this interaction leads to RBBP8 proteasomal degradation (PubMed:27561354). Directly interacts with PIN1; this interaction depends upon RBBP8 phosphorylation, predominantly at Thr-315 (PubMed:23623683). Interacts with FZR1; this interaction leads to APC/C-mediated RBBP8 proteasomal degradation (PubMed:25349192). Interacts with AUNIP; leading to recruit RBBP8 to sites of DNA damage (PubMed:29042561, PubMed:10764811, PubMed:11751867, PubMed:14654780, PubMed:15084581, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:19759395, PubMed:23623683, PubMed:25349192, PubMed:26502057, PubMed:26807646, PubMed:27561354, PubMed:9535825, PubMed:9721205). Interacts with SAMHD1 (PubMed:28834754). {ECO:0000269\|PubMed:10764811, ECO:0000269\|PubMed:11751867, ECO:0000269\|PubMed:14654780, ECO:0000269\|PubMed:15084581, ECO:0000269\|PubMed:15485915, ECO:0000269\|PubMed:16818604, ECO:0000269\|PubMed:17965729, ECO:0000269\|PubMed:19759395, ECO:0000269\|PubMed:23623683, ECO:0000269\|PubMed:25349192, ECO:0000269\|PubMed:26502057, ECO:0000269\|PubMed:26807646, ECO:0000269\|PubMed:27561354, ECO:0000269\|PubMed:28834754, ECO:0000269\|PubMed:29042561, ECO:0000269\|PubMed:9535825, ECO:0000269\|PubMed:9721205}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:10764811, ECO:0000269\|PubMed:17965729, ECO:0000269\|PubMed:23623683}. Chromosome {ECO:0000269\|PubMed:10764811, ECO:0000269\|PubMed:16818604, ECO:0000269\|PubMed:29042561}. Note=Associates with sites of DNA damage in S/G2 phase (PubMed:10764811, PubMed:25349192). Ubiquitinated RBBP8 binds to chromatin following DNA damage (PubMed:16818604). {ECO:0000269\|PubMed:10764811, ECO:0000269\|PubMed:16818604, ECO:0000269\|PubMed:25349192}.
Tissue specificity:		Expressed in ER-positive breast cancer lines, but tends to be down-regulated ER-negative cells (at protein level). {ECO:0000269\|PubMed:18171986}.
Induction:		Expression is cell-cycle regulated. Levels increase as dividing cells traverse the G1/S boundary (PubMed:18171986). The protein is degraded by the proteasome pathway during mitotic exit. Also degraded in response to DNA damage in G2 cells; this degradation is mediated by the E3 FZR1/APC/C complex (PubMed:25349192). {ECO:0000269\|PubMed:18171986, ECO:0000269\|PubMed:25349192}.
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:		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). {ECO:0000269\|PubMed:10910365, ECO:0000269\|PubMed:15485915, ECO:0000269\|PubMed:17965729, ECO:0000269\|PubMed:19202191, ECO:0000269\|PubMed:23623683}.
Ptm:		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). {ECO:0000269\|PubMed:14654780, ECO:0000269\|PubMed:16818604, ECO:0000269\|PubMed:25349192, ECO:0000269\|PubMed:26502057, ECO:0000269\|PubMed:27561354}.
Disease:		Seckel syndrome 2 (SCKL2) [MIM:606744]: 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. {ECO:0000269\|PubMed:21998596, ECO:0000269\|PubMed:24389050}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Jawad syndrome (JWDS) [MIM:251255]: A syndrome characterized by congenital microcephaly, moderately severe mental retardation, 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. {ECO:0000269\|PubMed:21998596}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Note=Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk (PubMed:21799032). Associated with sensitivity to tamoxifen in certain breast cancer cell lines (PubMed:18171986). {ECO:0000269\|PubMed:18171986, ECO:0000269\|PubMed:21799032}.
Similarity:		Belongs to the COM1/SAE2/CtIP family. {ECO:0000305}.