Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair

Peake, Jasmine D.; Noguchi, Eishi

doi:10.1007/s00439-022-02462-9

Cited by 61 publications

(47 citation statements)

References 246 publications

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“…Fanconi anemia is a rare genetic disorder characterized by physical abnormalities (e.g., short stature, irregular skin coloring, skeletal malformations), bone marrow failure, and an increased risk of certain malignancies (e.g., acute myeloid leukemia, head and neck squamous cell carcinomas) [68]. At least 23 different genes are associated with Fanconi anemia, including BRCA1 , BRCA2 , FANCI , FANCD2 , XPF , and SLX4 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Aprosoff

Dyakov

Cheung

et al. 2022

Preprint

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The DNA repair scaffold SLX4 has pivotal roles in cellular processes that maintain genome stability, most notably homologous recombination. Germline mutations in SLX4 are associated with Fanconi anemia, a disease characterized by chromosome instability and cancer susceptibility. The role of mammalian SLX4 in homologous recombination depends critically on binding and activating structure-selective endonucleases, namely SLX1, MUS81-EME1, and XPF-ERCC1. Increasing evidence indicates that cells rely on distinct SLX4-dependent complexes to remove DNA lesions in specific regions of the genome. Despite our understanding of SLX4 as a scaffold for DNA repair proteins, a detailed repertoire of SLX4 interactors has never been reported. Here, we provide the first comprehensive map of the human SLX4 interactome using proximity-dependent biotin identification (BioID) and affinity purification coupled to mass spectrometry (AP-MS). We identified 237 high-confidence interactors, of which the vast majority represent novel SLX4 binding proteins. Network analysis of these hits revealed pathways with known involvement of SLX4, such as DNA repair, and novel or emerging pathways of interest, including RNA metabolism and chromatin remodeling. In summary, the comprehensive SLX4 interactome we report here provides a deeper understanding of how SLX4 functions in DNA repair while revealing new cellular processes that may involve SLX4.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Aprosoff

Dyakov

Cheung

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Fanconi anemia is a rare genetic disorder characterized by physical abnormalities (e.g., short stature, irregular skin coloring, skeletal malformations), bone marrow failure, and an increased risk of certain malignancies (e.g., acute myeloid leukemia, head and neck squamous cell carcinomas) . At least 23 different genes are associated with Fanconi anemia, including BRCA1 , BRCA2 , FANCI , FANCD2 , XPF , and SLX4 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 Using Proximity Labeling and Affinity Purification

et al. 2023

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The DNA repair scaffold SLX4 has pivotal roles in cellular processes that maintain genome stability, most notably homologous recombination. Germline mutations in SLX4 are associated with Fanconi anemia, a disease characterized by chromosome instability and cancer susceptibility. The role of mammalian SLX4 in homologous recombination depends critically on binding and activating structure-selective endonucleases, namely SLX1, MUS81-EME1, and XPF-ERCC1. Increasing evidence indicates that cells rely on distinct SLX4-dependent complexes to remove DNA lesions in specific regions of the genome. Despite our understanding of SLX4 as a scaffold for DNA repair proteins, a detailed repertoire of SLX4 interactors has never been reported. Here, we provide a comprehensive map of the human SLX4 interactome using proximity-dependent biotin identification (BioID) and affinity purification coupled to mass spectrometry (AP-MS). We identified 221 unique high-confidence interactors, of which the vast majority represent novel SLX4-binding proteins. Network analysis of these hits revealed pathways with known involvement of SLX4, such as DNA repair, and several emerging pathways of interest, including RNA metabolism and chromatin remodeling. In summary, the comprehensive SLX4 interactome we report here provides a deeper understanding of how SLX4 functions in DNA repair while revealing new cellular processes that may involve SLX4.

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“…Pathogenic variants in FANCG and FANCD2 genes have a pathogenic variant frequency of 8% and 4%, respectively, and have shown to exert an autosomal recessive effect [ 28 ]. Monoallelic pathogenic variants in FANCD1/BRCA2 , FANCS/BRCA1 , FANCJ/BRIP1 , FANCM , FANCN/PALB2 , and FANCO/RAD51C have been linked to familial breast and ovarian cancer [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru

Zavaleta-Lopez¹,

Solis²,

Palacios

et al. 2022

Cancers

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Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T>C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance.

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Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair

Cited by 61 publications

References 246 publications

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 Using Proximity Labeling and Affinity Purification

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru

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