* 605882

BRCA1-INTERACTING PROTEIN 1; BRIP1


Alternative titles; symbols

BRCA1-ASSOCIATED C-TERMINAL HELICASE 1; BACH1
DELETIONS OF GUANINE-RICH DNA, C. ELEGANS, HOMOLOG OF
DOG1, HOMOLOG OF
FANCJ GENE; FANCJ


HGNC Approved Gene Symbol: BRIP1

Cytogenetic location: 17q23.2     Genomic coordinates (GRCh38): 17:61,679,139-61,863,528 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
17q23.2 {Breast cancer, early-onset, susceptibility to} 114480 AD, SMu 3
Fanconi anemia, complementation group J 609054 3

TEXT

Cloning and Expression

Cantor et al. (2001) showed that BRCA1 (113705) interacts in vivo with a novel protein, BRIP1, which they called BACH1 (BRCA1-associated C-terminal helicase-1), a member of the DEAH helicase family. The predicted 1,249-amino acid BRIP1 protein contains the 7 helicase-specific motifs that are conserved among members of the DEAH family, and the helicase domain includes a nuclear localization signal. Northern blot analysis revealed ubiquitous expression of BRIP1, with highest levels in testis, an expression pattern similar to that of BRCA1.


Gene Function

Cantor et al. (2001) demonstrated that BRIP1 binds directly to the BRCT repeats of BRCA1. A BRIP1 derivative, bearing a mutation in a residue that is essential for catalytic function in other helicases, interfered with normal double-strand break repair in a manner that was dependent on its BRCA1-binding function. Thus, the authors concluded that BRIP1-BRCA1 complex formation contributes to a key BRCA1 activity.

Genes that contribute to tumorigenesis can be broadly classified as either gatekeepers or caretakers (Kinzler and Vogelstein, 1997). Genes in the gatekeeper class directly regulate cell division or cell death, and their alteration results in the uncontrolled cellular proliferation that characterizes tumor cells. Genes in the caretaker class are involved in DNA metabolic processes and are responsible for maintaining the overall stability of the genome. The inherent stability of DNA sequences varies widely, with some types of sequences being classified as 'at risk motifs' (ARMs) that are particularly prone to accumulating mutations or promoting genome rearrangements. One structural feature of intact genomes is runs of homopolymeric dC/dG. Cheung et al. (2002) described an unusual mutator phenotype in Caenorhabditis elegans characterized by deletions that start around the 3-prime end of polyguanine tracts and terminate at variable positions 5-prime from such tracts. They observed deletions throughout genomic DNA in about half of polyguanine tracts examined, especially those containing 22 or more consecutive guanine nucleotides. The mutator phenotype resulted from disruption of a gene that encodes a protein with characteristics of a DEAH helicase, which Cheung et al. (2002) named dog1 (deletions of guanine-rich DNA). Nematodes mutated in dog1 showed germline as well as somatic deletions in genes containing polyguanine tracts. They proposed that dog1 is required to resolve the secondary structures of guanine-rich DNA that occasionally form during lagging-strand DNA synthesis. Jinks-Robertson (2002), who referred to dog1 as 'the genome's best friend,' pointed to BACH1 as the structurally most closely related protein in humans and raised the possibility that targeted mutations in BACH1 might show the mutational signature seen in dog1 mutant nematodes.

Yu et al. (2003) demonstrated that the BRCT domain of BRCA1 directly interacts with phosphorylated BACH1. The specific interaction between BRCA1 and phosphorylated BACH1 is cell cycle regulated and is required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Further, Yu et al. (2003) showed that 2 other BRCT domains interact with their respective physiologic partners in a phosphorylation-dependent manner. Thirteen additional BRCT domains also preferentially bind phosphopeptides rather than nonphosphorylated control peptides. Yu et al. (2003) concluded that their data implied that the BRCT domain is a phosphoprotein-binding domain involved in cell cycle control.

Cantor et al. (2004) determined that BRIP1 is both a DNA-dependent ATPase and a 5-prime-to-3-prime DNA helicase. Helicase activity was strictly ATP dependent and was inhibited by the addition of EDTA, consistent with a requirement for cations. BRIP1 unwound DNA:DNA substrates and RNA:DNA hybrid substrates, but it did not unwind double-stranded RNA. BRIP1 carrying a lys52-to-arg mutation lacked ATPase activity, failed to be stimulated by single-stranded DNA, and was inactive in an unwinding assay. BRIP1 with the clinically relevant mutation pro47 to ala (P47A; 605882.0001) showed no detectable ATPase activity and complete loss of function, whereas BRIP1 with the clinically relevant mutation met299 to ile (M299I; 605882.0002) showed elevated ATPase activity, but had limited ability to unwind DNA substrates of more than 19 basepairs.

Bridge et al. (2005) cloned the chicken ortholog of BRIP1 and established a homologous knockout in the avian B-cell line DT40. The phenotype of these brip1 mutant cells in response to DNA damage differed from that of brca1 mutant cells and more closely resembled that of fancc (613899) mutant cells, with a profound sensitivity to the DNA-crosslinking agent cisplatin and acute cell-cycle arrest in late S-G2 phase. These defects were corrected by expression of human BRIP1 lacking the BRCT interaction domain. Moreover, in human cells exposed to mitomycin C, short interfering RNA-mediated knockdown of BRIP1 led to a substantial increase in chromosome aberrations, a characteristic phenotype of cells derived from individuals with Fanconi anemia (see FANCJ; 609054). Because brip1 mutant cells are proficient for the ubiquitination of FANCD2 protein (613984), these data indicated that brip1 has a function in the Fanconi anemia pathway that is independent of BRCA1 and downstream of FANCD2 activation.

Gupta et al. (2007) found that FANCJ immunoprecipitated with RPA (see RPA70, or RPA1; 179835), a multiprotein single-stranded DNA-binding complex implicated in DNA replication and repair. FANCJ and RPA colocalized in nuclear foci after DNA damage or replication stress. FANCJ and RPA bound with high affinity via the RPA70 subunit. Although FANCJ showed limited ability to unwind even a 47-bp forked duplex, the presence of RPA enabled FANCJ to act as a much more processive helicase.


Mapping

By genomic analysis, Cantor et al. (2001) mapped the BRIP1 gene to chromosome 17q22.


Molecular Genetics

Susceptibility to Breast Cancer

Cantor et al. (2001) identified germline BRIP1 mutations affecting the helicase domain in 2 of 65 patients with early-onset breast cancer (114480), of whom 35 had a strong family history of breast and/or ovarian cancer but lacked mutations in either the BRCA1 or BRCA2 (600185) genes. The mutations were not found in 200 matched controls. The authors concluded that like BRCA1, BRIP1 may be a target of germline cancer-inducing mutations.

Seal et al. (2006) identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9 of 1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2 of 2,081 controls (p = 0.0030). They estimated that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2). Thus, as in the case of BRCA2, inactivating truncating mutations of BRIP1 cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers. Of note, biallelic mutations of the breast cancer susceptibility gene BRCA2 cause Fanconi anemia complementation group D1 (605724) (Litman et al., 2005).

Fanconi Anemia, Complementation Group J

Using genetic mapping, mutation identification, and Western blot data, Levran et al. (2005) identified the defective protein in FA-J cells (FANCJ; 609054) as BRIP1. Genome scans identified a statistically significant region of homozygosity of 6 Mb on 17q23. In this region, 2 affected Inuit sibs shared the same haplotype for 48 SNPs; the haplotype of another Inuit individual differed by only 1 SNP, leaving a 4.5-Mb region of shared haplotype among the Inuit individuals. Each of 2 Hispanic individuals had a unique haplotype; the extent of the homozygous region was different in each individual.

After numerous unsuccessful attempts to identify the gene mutated in FA-J (FANCJ), using a complementation cloning strategy, Levitus et al. (2005) attempted positional cloning. By means of a genomewide scan using closely positioned polymorphic markers, they identified the largest region of homozygosity on chromosome 17 and studied this region in more detail in informative families with FA-J. They also tested chromosome 17 for complementation of the Fanconi anemia defect by microcell-mediated chromosome transfer. Boundaries of the chromosome 17 fragment and information from the genomewide screen in genetically informative families narrowed the FANCJ candidate region. They found that BRIP1 resided in the critical linkage region and considered it a good candidate because chicken DT40 cells lacking BRIP1 expression have a Fanconi anemia-like phenotype. They sequenced this gene in families with FA-J and identified mutation in all affected individuals that segregated with disease status in informative families. They found a recurrent nonsense mutation, R798X in exon 17 (605882.0003), in 5 alleles from 4 individuals of diverse geographic origin, suggesting that it might be a hotspot or an ancient mutation. All other mutations were private.

Susceptibility to Ovarian Cancer

For discussion of a possible association between susceptibility to ovarian cancer and variation in the BRIP1 gene, see 167000.


ALLELIC VARIANTS ( 4 Selected Examples):

.0001 BREAST CANCER, EARLY-ONSET

BRIP1, PRO47ALA
  
RCV000005002...

Cantor et al. (2001) identified a heterozygous C-to-G transversion at nucleotide 139 of the BRIP1 gene, resulting in a pro47-to-ala mutation, in an individual with early-onset breast cancer (114480) and a family history of breast and ovarian cancer. This mutation occurred in the helicase domain of the BRIP1 protein and was not found in 200 controls.


.0002 BREAST CANCER, EARLY-ONSET

BRIP1, MET299ILE
  
RCV000005003...

Cantor et al. (2001) identified a heterozygous G-to-A transition at nucleotide 897 of the BRIP1 gene, resulting in a met299-to-ile mutation, in an individual with early-onset breast cancer (114480) and a family history of breast and ovarian cancer. This mutation occurred in the helicase domain of the BRIP1 protein and was not found in 200 controls.


.0003 FANCONI ANEMIA, COMPLEMENTATION GROUP J

BRIP1, ARG798TER
  
RCV000005004...

In 10 unrelated individuals with Fanconi anemia complementation group J (FANCJ; 609054), Levran et al. (2005) found either homozygosity or compound heterozygosity for the nonsense mutation arg798 to ter (R798X) in the BRIP1 gene. Three of the 10 individuals were compound heterozygotes. The diverse ethnicity included Hispanic, European American, Irish Traveller, and Inuit. Phenotypic and hematologic abnormalities in these 10 affected families included growth retardation, cafe-au-lait spots, microphthalmia, thumb and kidney abnormalities, hearing loss, and bone marrow failure beginning between 2 and 6.5 years.

Levitus et al. (2005) found the R798X mutation in 5 alleles from 4 individuals with Fanconi anemia complementation group J of diverse geographic origin: Canada, United Kingdom, Kuwait, and the United States.


.0004 FANCONI ANEMIA, COMPLEMENTATION GROUP J

BRIP1, ALA349PRO
  
RCV000023492...

In a stillborn fetus with a gestational age of 22 weeks and Fanconi anemia complementation group J (FANCJ; 609054), Levran et al. (2005) identified compound heterozygosity for mutations in the BRIP1 gene. The maternally inherited mutation was arg798 to ter (R798X; 605882.0003). The paternally inherited mutation was a G-to-C transversion at nucleotide 1186 in exon 8 of the BRIP1 gene, resulting in an ala349-to-pro (A349P) substitution. The fetus exhibited intrauterine growth retardation, radial and ulna aplasia, bilateral clubfeet, cleft palate, abnormal facies, and severe gastrointestinal, urogenital, cardiovascular, respiratory, and central nervous system abnormalities.

Wu et al. (2010) stated that BRIP1 ala349 resides immediately adjacent to a highly conserved cysteine of the predicted iron-sulfur (Fe-S) domain. They found that the recombinant wildtype BRIP1 protein possessed 3 Fe atoms per polypeptide, whereas BRIP1 A349P had only 1 Fe atom per polypeptide. BRIP1 A349P did not differ from wildtype recombinant BRIP1 in binding to various DNA substrates, ATPase activity, or ability to translocate along single-stranded DNA in an ATPase-dependent manner. However, unlike wildtype BRIP1, BRIP1 A349P lacked the ability to unwind forked duplex DNA, 3-stranded D-loop DNA, or G4 DNA, was not activated by RPA (see 179835), and was unable to displace RAD51 (179617) from single-stranded DNA. BRIP1 A349P failed to render cells resistant to the effects of the DNA crosslinking agent mitomycin C or the G4 DNA-binding agent telomestatin. Wu et al. (2010) concluded that BRIP1 A349P exerts a dominant-negative effect on cell survival or DNA damage accumulation after treatment with agents that induce DNA damage or cellular stress. They hypothesized that the mutation may disrupt the accumulation or activity of other DNA repair/checkpoint factors at stalled replication forks.


REFERENCES

  1. Bridge, W. L., Vandenberg, C. J., Franklin, R. J., Hiom, K. The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Nature Genet. 37: 953-957, 2005. [PubMed: 16116421, related citations] [Full Text]

  2. Cantor, S. B., Bell, D. W., Ganesan, S., Kass, E. M., Drapkin, R., Grossman, S., Wahrer, D. C. R., Sgroi, D. C., Lane, W. S., Haber, D. A., Livingston, D. M. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105: 149-160, 2001. [PubMed: 11301010, related citations] [Full Text]

  3. Cantor, S., Drapkin, R., Zhang, F., Lin, Y., Han, J., Pamidi, S., Livingston, D. M. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc. Nat. Acad. Sci. 101: 2357-2362, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 101: 6834 only, 2004. [PubMed: 14983014, images, related citations] [Full Text]

  4. Cheung, I., Schertzer, M., Rose, A., Lansdorp, P. M. Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nature Genet. 31: 405-409, 2002. [PubMed: 12101400, related citations] [Full Text]

  5. Gupta, R., Sharma, S., Sommers, J. A., Kenny, M. K., Cantor, S. B., Brosh, R. M., Jr. FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein. Blood 110: 2390-2398, 2007. [PubMed: 17596542, images, related citations] [Full Text]

  6. Jinks-Robertson, S. The genome's best friend. Nature Genet. 31: 331-332, 2002. [PubMed: 12101401, related citations] [Full Text]

  7. Kinzler, K. W., Vogelstein, B. Gatekeepers and caretakers. Nature 386: 761-763, 1997. [PubMed: 9126728, related citations] [Full Text]

  8. Levitus, M., Waisfisz, Q., Godthelp, B. C., de Vries, Y., Hussain, S., Wiegant, W. W., Elghalbzouri-Maghrani, E., Steltenpool, J., Rooimans, M. A., Pals, G., Arwert, F., Mathew, C. G., Zdzienicka, M. Z., Hiom, K., De Winter, J. P., Joenje, H. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nature Genet. 37: 934-935, 2005. [PubMed: 16116423, related citations] [Full Text]

  9. Levran, O., Attwooll, C., Henry, R. T., Milton, K. L., Neveling, K., Rio, P., Batish, S. D., Kalb, R., Velleur, E., Barral, S., Ott, J., Petrini, J., Schindler, D., Hanenberg, H., Auerbach, A. D. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nature Genet. 37: 931-933, 2005. Note: Addendum: Nature Genet. 37: 1296 only, 2005. [PubMed: 16116424, related citations] [Full Text]

  10. Litman, R., Peng, M., Jin, Z., Zhang, F., Zhang, J., Powell, S., Andreassen P. R., Cantor, S. B. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8: 255-265, 2005. [PubMed: 16153896, related citations] [Full Text]

  11. Seal, S., Thompson, D., Renwick, A., Elliott, A., Kelly, P., Barfoot, R., Chagtai, T., Jayatilake, H., Ahmed, M., Spanova, K., North, B., McGuffog, L., Evans, D. G., Eccles, D., Breast Cancer Susceptibility Collaboration (UK), Easton, D. F., Stratton, M. R., Rahman, N. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nature Genet. 38: 1239-1241, 2006. [PubMed: 17033622, related citations] [Full Text]

  12. Wu, Y., Sommers, J. A., Suhasini, A. N., Leonard, T., Deakyne, J. S., Mazin, A. V., Shin-ya, K., Kitao, H., Brosh, R. M., Jr. Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes. Blood 116: 3780-3791, 2010. [PubMed: 20639400, images, related citations] [Full Text]

  13. Yu, X., Chini, C. C. S., He, M., Mer, G., Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302: 639-642, 2003. [PubMed: 14576433, related citations] [Full Text]


Matthew B. Gross - updated : 9/6/2011
Patricia A. Hartz - updated : 7/11/2011
Patricia A. Hartz - updated : 6/18/2008
Victor A. McKusick - updated : 11/21/2006
Victor A. McKusick - updated : 11/17/2005
Victor A. McKusick - updated : 10/6/2005
Patricia A. Hartz - updated : 3/16/2004
Ada Hamosh - updated : 11/11/2003
Victor A. McKusick - updated : 8/1/2002
Creation Date:
Stylianos E. Antonarakis : 4/26/2001
carol : 04/19/2019
carol : 07/06/2016
terry : 11/13/2012
alopez : 7/26/2012
alopez : 7/26/2012
terry : 7/23/2012
mgross : 9/6/2011
mgross : 9/6/2011
terry : 7/11/2011
wwang : 6/24/2011
ckniffin : 5/10/2010
mgross : 6/19/2008
terry : 6/18/2008
wwang : 12/1/2006
alopez : 11/28/2006
terry : 11/21/2006
carol : 8/31/2006
alopez : 11/21/2005
terry : 11/17/2005
alopez : 10/11/2005
alopez : 10/10/2005
alopez : 10/10/2005
terry : 10/6/2005
mgross : 3/23/2004
terry : 3/16/2004
terry : 1/2/2003
alopez : 8/1/2002
mgross : 4/26/2001

* 605882

BRCA1-INTERACTING PROTEIN 1; BRIP1


Alternative titles; symbols

BRCA1-ASSOCIATED C-TERMINAL HELICASE 1; BACH1
DELETIONS OF GUANINE-RICH DNA, C. ELEGANS, HOMOLOG OF
DOG1, HOMOLOG OF
FANCJ GENE; FANCJ


HGNC Approved Gene Symbol: BRIP1

Cytogenetic location: 17q23.2     Genomic coordinates (GRCh38): 17:61,679,139-61,863,528 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
17q23.2 {Breast cancer, early-onset, susceptibility to} 114480 Autosomal dominant; Somatic mutation 3
Fanconi anemia, complementation group J 609054 3

TEXT

Cloning and Expression

Cantor et al. (2001) showed that BRCA1 (113705) interacts in vivo with a novel protein, BRIP1, which they called BACH1 (BRCA1-associated C-terminal helicase-1), a member of the DEAH helicase family. The predicted 1,249-amino acid BRIP1 protein contains the 7 helicase-specific motifs that are conserved among members of the DEAH family, and the helicase domain includes a nuclear localization signal. Northern blot analysis revealed ubiquitous expression of BRIP1, with highest levels in testis, an expression pattern similar to that of BRCA1.


Gene Function

Cantor et al. (2001) demonstrated that BRIP1 binds directly to the BRCT repeats of BRCA1. A BRIP1 derivative, bearing a mutation in a residue that is essential for catalytic function in other helicases, interfered with normal double-strand break repair in a manner that was dependent on its BRCA1-binding function. Thus, the authors concluded that BRIP1-BRCA1 complex formation contributes to a key BRCA1 activity.

Genes that contribute to tumorigenesis can be broadly classified as either gatekeepers or caretakers (Kinzler and Vogelstein, 1997). Genes in the gatekeeper class directly regulate cell division or cell death, and their alteration results in the uncontrolled cellular proliferation that characterizes tumor cells. Genes in the caretaker class are involved in DNA metabolic processes and are responsible for maintaining the overall stability of the genome. The inherent stability of DNA sequences varies widely, with some types of sequences being classified as 'at risk motifs' (ARMs) that are particularly prone to accumulating mutations or promoting genome rearrangements. One structural feature of intact genomes is runs of homopolymeric dC/dG. Cheung et al. (2002) described an unusual mutator phenotype in Caenorhabditis elegans characterized by deletions that start around the 3-prime end of polyguanine tracts and terminate at variable positions 5-prime from such tracts. They observed deletions throughout genomic DNA in about half of polyguanine tracts examined, especially those containing 22 or more consecutive guanine nucleotides. The mutator phenotype resulted from disruption of a gene that encodes a protein with characteristics of a DEAH helicase, which Cheung et al. (2002) named dog1 (deletions of guanine-rich DNA). Nematodes mutated in dog1 showed germline as well as somatic deletions in genes containing polyguanine tracts. They proposed that dog1 is required to resolve the secondary structures of guanine-rich DNA that occasionally form during lagging-strand DNA synthesis. Jinks-Robertson (2002), who referred to dog1 as 'the genome's best friend,' pointed to BACH1 as the structurally most closely related protein in humans and raised the possibility that targeted mutations in BACH1 might show the mutational signature seen in dog1 mutant nematodes.

Yu et al. (2003) demonstrated that the BRCT domain of BRCA1 directly interacts with phosphorylated BACH1. The specific interaction between BRCA1 and phosphorylated BACH1 is cell cycle regulated and is required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Further, Yu et al. (2003) showed that 2 other BRCT domains interact with their respective physiologic partners in a phosphorylation-dependent manner. Thirteen additional BRCT domains also preferentially bind phosphopeptides rather than nonphosphorylated control peptides. Yu et al. (2003) concluded that their data implied that the BRCT domain is a phosphoprotein-binding domain involved in cell cycle control.

Cantor et al. (2004) determined that BRIP1 is both a DNA-dependent ATPase and a 5-prime-to-3-prime DNA helicase. Helicase activity was strictly ATP dependent and was inhibited by the addition of EDTA, consistent with a requirement for cations. BRIP1 unwound DNA:DNA substrates and RNA:DNA hybrid substrates, but it did not unwind double-stranded RNA. BRIP1 carrying a lys52-to-arg mutation lacked ATPase activity, failed to be stimulated by single-stranded DNA, and was inactive in an unwinding assay. BRIP1 with the clinically relevant mutation pro47 to ala (P47A; 605882.0001) showed no detectable ATPase activity and complete loss of function, whereas BRIP1 with the clinically relevant mutation met299 to ile (M299I; 605882.0002) showed elevated ATPase activity, but had limited ability to unwind DNA substrates of more than 19 basepairs.

Bridge et al. (2005) cloned the chicken ortholog of BRIP1 and established a homologous knockout in the avian B-cell line DT40. The phenotype of these brip1 mutant cells in response to DNA damage differed from that of brca1 mutant cells and more closely resembled that of fancc (613899) mutant cells, with a profound sensitivity to the DNA-crosslinking agent cisplatin and acute cell-cycle arrest in late S-G2 phase. These defects were corrected by expression of human BRIP1 lacking the BRCT interaction domain. Moreover, in human cells exposed to mitomycin C, short interfering RNA-mediated knockdown of BRIP1 led to a substantial increase in chromosome aberrations, a characteristic phenotype of cells derived from individuals with Fanconi anemia (see FANCJ; 609054). Because brip1 mutant cells are proficient for the ubiquitination of FANCD2 protein (613984), these data indicated that brip1 has a function in the Fanconi anemia pathway that is independent of BRCA1 and downstream of FANCD2 activation.

Gupta et al. (2007) found that FANCJ immunoprecipitated with RPA (see RPA70, or RPA1; 179835), a multiprotein single-stranded DNA-binding complex implicated in DNA replication and repair. FANCJ and RPA colocalized in nuclear foci after DNA damage or replication stress. FANCJ and RPA bound with high affinity via the RPA70 subunit. Although FANCJ showed limited ability to unwind even a 47-bp forked duplex, the presence of RPA enabled FANCJ to act as a much more processive helicase.


Mapping

By genomic analysis, Cantor et al. (2001) mapped the BRIP1 gene to chromosome 17q22.


Molecular Genetics

Susceptibility to Breast Cancer

Cantor et al. (2001) identified germline BRIP1 mutations affecting the helicase domain in 2 of 65 patients with early-onset breast cancer (114480), of whom 35 had a strong family history of breast and/or ovarian cancer but lacked mutations in either the BRCA1 or BRCA2 (600185) genes. The mutations were not found in 200 matched controls. The authors concluded that like BRCA1, BRIP1 may be a target of germline cancer-inducing mutations.

Seal et al. (2006) identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9 of 1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2 of 2,081 controls (p = 0.0030). They estimated that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2). Thus, as in the case of BRCA2, inactivating truncating mutations of BRIP1 cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers. Of note, biallelic mutations of the breast cancer susceptibility gene BRCA2 cause Fanconi anemia complementation group D1 (605724) (Litman et al., 2005).

Fanconi Anemia, Complementation Group J

Using genetic mapping, mutation identification, and Western blot data, Levran et al. (2005) identified the defective protein in FA-J cells (FANCJ; 609054) as BRIP1. Genome scans identified a statistically significant region of homozygosity of 6 Mb on 17q23. In this region, 2 affected Inuit sibs shared the same haplotype for 48 SNPs; the haplotype of another Inuit individual differed by only 1 SNP, leaving a 4.5-Mb region of shared haplotype among the Inuit individuals. Each of 2 Hispanic individuals had a unique haplotype; the extent of the homozygous region was different in each individual.

After numerous unsuccessful attempts to identify the gene mutated in FA-J (FANCJ), using a complementation cloning strategy, Levitus et al. (2005) attempted positional cloning. By means of a genomewide scan using closely positioned polymorphic markers, they identified the largest region of homozygosity on chromosome 17 and studied this region in more detail in informative families with FA-J. They also tested chromosome 17 for complementation of the Fanconi anemia defect by microcell-mediated chromosome transfer. Boundaries of the chromosome 17 fragment and information from the genomewide screen in genetically informative families narrowed the FANCJ candidate region. They found that BRIP1 resided in the critical linkage region and considered it a good candidate because chicken DT40 cells lacking BRIP1 expression have a Fanconi anemia-like phenotype. They sequenced this gene in families with FA-J and identified mutation in all affected individuals that segregated with disease status in informative families. They found a recurrent nonsense mutation, R798X in exon 17 (605882.0003), in 5 alleles from 4 individuals of diverse geographic origin, suggesting that it might be a hotspot or an ancient mutation. All other mutations were private.

Susceptibility to Ovarian Cancer

For discussion of a possible association between susceptibility to ovarian cancer and variation in the BRIP1 gene, see 167000.


ALLELIC VARIANTS 4 Selected Examples):

.0001   BREAST CANCER, EARLY-ONSET

BRIP1, PRO47ALA
SNP: rs28903098, gnomAD: rs28903098, ClinVar: RCV000005002, RCV000116124, RCV000199377, RCV000200979, RCV000409748, RCV000410864, RCV000587908, RCV000778130, RCV000990044, RCV001090025, RCV003149563

Cantor et al. (2001) identified a heterozygous C-to-G transversion at nucleotide 139 of the BRIP1 gene, resulting in a pro47-to-ala mutation, in an individual with early-onset breast cancer (114480) and a family history of breast and ovarian cancer. This mutation occurred in the helicase domain of the BRIP1 protein and was not found in 200 controls.


.0002   BREAST CANCER, EARLY-ONSET

BRIP1, MET299ILE
SNP: rs137852985, ClinVar: RCV000005003, RCV000582137, RCV000636166

Cantor et al. (2001) identified a heterozygous G-to-A transition at nucleotide 897 of the BRIP1 gene, resulting in a met299-to-ile mutation, in an individual with early-onset breast cancer (114480) and a family history of breast and ovarian cancer. This mutation occurred in the helicase domain of the BRIP1 protein and was not found in 200 controls.


.0003   FANCONI ANEMIA, COMPLEMENTATION GROUP J

BRIP1, ARG798TER
SNP: rs137852986, gnomAD: rs137852986, ClinVar: RCV000005004, RCV000116139, RCV000205436, RCV000212324, RCV000312325, RCV000409918, RCV000504276, RCV000515368, RCV000778127, RCV000989994, RCV001355458, RCV001535465, RCV003149564, RCV003155909, RCV003162209

In 10 unrelated individuals with Fanconi anemia complementation group J (FANCJ; 609054), Levran et al. (2005) found either homozygosity or compound heterozygosity for the nonsense mutation arg798 to ter (R798X) in the BRIP1 gene. Three of the 10 individuals were compound heterozygotes. The diverse ethnicity included Hispanic, European American, Irish Traveller, and Inuit. Phenotypic and hematologic abnormalities in these 10 affected families included growth retardation, cafe-au-lait spots, microphthalmia, thumb and kidney abnormalities, hearing loss, and bone marrow failure beginning between 2 and 6.5 years.

Levitus et al. (2005) found the R798X mutation in 5 alleles from 4 individuals with Fanconi anemia complementation group J of diverse geographic origin: Canada, United Kingdom, Kuwait, and the United States.


.0004   FANCONI ANEMIA, COMPLEMENTATION GROUP J

BRIP1, ALA349PRO
SNP: rs149364097, gnomAD: rs149364097, ClinVar: RCV000023492, RCV000120412, RCV000131544, RCV000216316, RCV000466014, RCV000761010, RCV002271374, RCV003335053, RCV003389672

In a stillborn fetus with a gestational age of 22 weeks and Fanconi anemia complementation group J (FANCJ; 609054), Levran et al. (2005) identified compound heterozygosity for mutations in the BRIP1 gene. The maternally inherited mutation was arg798 to ter (R798X; 605882.0003). The paternally inherited mutation was a G-to-C transversion at nucleotide 1186 in exon 8 of the BRIP1 gene, resulting in an ala349-to-pro (A349P) substitution. The fetus exhibited intrauterine growth retardation, radial and ulna aplasia, bilateral clubfeet, cleft palate, abnormal facies, and severe gastrointestinal, urogenital, cardiovascular, respiratory, and central nervous system abnormalities.

Wu et al. (2010) stated that BRIP1 ala349 resides immediately adjacent to a highly conserved cysteine of the predicted iron-sulfur (Fe-S) domain. They found that the recombinant wildtype BRIP1 protein possessed 3 Fe atoms per polypeptide, whereas BRIP1 A349P had only 1 Fe atom per polypeptide. BRIP1 A349P did not differ from wildtype recombinant BRIP1 in binding to various DNA substrates, ATPase activity, or ability to translocate along single-stranded DNA in an ATPase-dependent manner. However, unlike wildtype BRIP1, BRIP1 A349P lacked the ability to unwind forked duplex DNA, 3-stranded D-loop DNA, or G4 DNA, was not activated by RPA (see 179835), and was unable to displace RAD51 (179617) from single-stranded DNA. BRIP1 A349P failed to render cells resistant to the effects of the DNA crosslinking agent mitomycin C or the G4 DNA-binding agent telomestatin. Wu et al. (2010) concluded that BRIP1 A349P exerts a dominant-negative effect on cell survival or DNA damage accumulation after treatment with agents that induce DNA damage or cellular stress. They hypothesized that the mutation may disrupt the accumulation or activity of other DNA repair/checkpoint factors at stalled replication forks.


REFERENCES

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Contributors:
Matthew B. Gross - updated : 9/6/2011
Patricia A. Hartz - updated : 7/11/2011
Patricia A. Hartz - updated : 6/18/2008
Victor A. McKusick - updated : 11/21/2006
Victor A. McKusick - updated : 11/17/2005
Victor A. McKusick - updated : 10/6/2005
Patricia A. Hartz - updated : 3/16/2004
Ada Hamosh - updated : 11/11/2003
Victor A. McKusick - updated : 8/1/2002

Creation Date:
Stylianos E. Antonarakis : 4/26/2001

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