Functional Interplay between BRCA2/FancD1 and FancC in DNA Repair

Kitao, Hiroyuki; Yamamoto, Kazuhiko; Matsushita, Nobuko; Ohzeki, Mioko; Ishiai, Masamichi; Takata, Minoru

doi:10.1074/jbc.m603290200

Cited by 37 publications

(39 citation statements)

References 51 publications

(50 reference statements)

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“…This is similar to observations that, following DNA damage induction, a majority of GFP-FANCD2 and RAD51 foci colocalized although RAD51 and FANCD2 foci formation are independent events (27), and that monoubiquitinated FANCD2 and BRCA2/FANCD1 colocalize in DNA damage-inducible foci (28). Together these data indicate that FANCD2 and RFWD3, RAD51, and BRCA2/FANCD1 converge and accumulate at the same DNA damage sites.…”

Section: Resultssupporting

confidence: 76%

“…A similar observation has been made in DT40 cells that were double-mutant for FANCC whole gene deletion and BRCA2 C-terminal deletion. Such Fancc/ Brca2ΔCTD double-mutant cells showed a more severe level of sensitivity to cisplatin and MMC compared with either of the single mutants (27). The additive sensitivity indicates that FANCD2 and RFWD3, or FANCC and BRCA2, may have some nonoverlapping functions in ICL repair.…”

Section: Resultsmentioning

confidence: 99%

“…Both variants are rare. They have not been reported in the 1000 Genomes Project (27,478 samples, February 2017) or in the Exome Aggregation Consortium (ExAC) database (60,706 samples, February 2017). Both variants were classified as probably damaging by several in silico prediction software tools.…”

Section: Whole Exome Sequencing Identifies Biallelic Mutations Of Rfwd3mentioning

confidence: 99%

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Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

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177

171

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The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G 2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Whole Exome Sequencing Identifies Biallelic Mutations Of Rfwd3mentioning

confidence: 99%

See 1 more Smart Citation

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

Self Cite

177

171

View full text Add to dashboard Cite

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“…The functions of FANCC are not yet totally clear. FANCC does not colocalize with BRCA1, BRCA2, and RAD51 in DNA repair foci to regulate DNA repair (27), and although it is part of the FA nuclear ''core complex'' necessary for FANCD2 and FANCDI monoubiquitination (28,29), it seems to have additional functions independent of other FA proteins (30), in particular, regulation of apoptosis (31).…”

Section: Discussionmentioning

confidence: 99%

Genetic Heterogeneity among Fanconi Anemia Heterozygotes and Risk of Cancer

et al. 2007

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Fanconi anemia (FA) is a rare autosomal recessive disease characterized by a greatly increased risk of cancer among those diagnosed with the syndrome. The question as to whether FA heterozygotes are at increased risk for cancer is of great importance to those at risk for being a carrier. To address this question, we formed a cohort of grandparents of probands identified through the International Fanconi Anemia Registry. We obtained informed consent, a short questionnaire, and either blood or buccal swab DNA. After diagnosis of the proband was confirmed and complementation studies or DNA sequencing on the proband were completed, mutation analyses of the putative carriers and noncarriers was carried out. Standardized incidence ratios (SIR) were calculated to compare the observed cancer incidence of the grandparents and other relatives with the expected rates of cancer, using the Surveillance, Epidemiology, and End Results registries and the Connecticut Cancer registry. In the 944 study subjects who participated (784 grandparents and 160 other relatives), there was no suggestion of an increase in overall cancer incidence. On the other hand, a significantly higher rate of breast cancer than expected was observed among carrier grandmothers [SIR, 1.7; 95% confidence interval (95% CI), 1.1-2.7]. Among the grandmothers, those who were carriers of FANCC mutations were found to be at highest risk (SIR, 2.4; 95% CI, 1.1-5.2). Overall, there was no increased risk for cancer among FA heterozygotes in this study of Fanconi relatives, although there is some evidence that FANCC mutations are possibly breast cancer susceptibility alleles. [Cancer Res 2007;67(19):9591-6]

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“…To date, 13 responsible FA genes have been identified [11][12][13][14][15][16][17][18][19][20][21][22][23][24]: eight of them (FANC-A, -B, -C, -E, -F, -G, -L and -M) code for proteins that form the multi-subunit nuclear FA core complex, two code for proteins that are activated by ubiquitinilation (FANC-I and -D2) and the last three interact with BRCA1 and predispose to breast cancer (FANC-N, -D1 and -J) [25,26]. Other proteins are also involved in the DNA repair pathway in relation with the function of the FA family of proteins, such as ATM, ATR [27], BRCA1 [28], H2AX [29] and USP1 [30].…”

Section: Introductionmentioning

confidence: 99%

The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features

Barroso

Pita

Arias

et al. 2009

Breast Cancer Res Treat

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International audienceFanconi anemia (FA) family of proteins participates in the DNA repair pathway by homologous recombination, and it is currently formed by 13 genes. Some of these proteins also confer susceptibility to hereditary breast and ovarian cancer (HBOC), since is the breast cancer susceptibility gene, and and explain 2% of non-BRCA1/2 HBOC families. Thus, there is an important connection between FA and BRCA pathways. In a previous case–control association study analysing , and , we reported an association between and sporadic breast cancer (BC) risk (OR = 1.35). In order to know whether variants in other FA genes could also be involved in this association, we have extended our study with the rest of FA genes and some others implicated in the BRCA pathway. We have also analyzed the correlation with survival, nodal metastasis and hormonal receptors (ER− and PR−). A total of 61 SNPs in ten FA genes (, , , , , , , , , ) and five FA related genes (, , , and ) were studied in a total of 547 consecutive and nonrelated sporadic BC cases and 552 unaffected controls from the Spanish population. Association analyses reported marginal statistically significant results with the minor allele of intronic SNPs in three genes: , , and . Survival association with SNPs on and genes were also reported. Sub-group analyses revealed associations between SNPs on and and nodal metastasis status and between and and PR− status

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Functional Interplay between BRCA2/FancD1 and FancC in DNA Repair

Cited by 37 publications

References 51 publications

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Genetic Heterogeneity among Fanconi Anemia Heterozygotes and Risk of Cancer

The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features

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