Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex

Otsuki, Tetsuya

doi:10.1093/hmg/10.23.2651

Cited by 80 publications

(45 citation statements)

References 76 publications

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“…FANCA has been reported to associate with the human ATP-dependent chromatin-remodeling complex, SWI/SNF (34). However, we failed to detect any human SWI/SNF components in the FAAPs (data not shown).…”

Section: Resultsmentioning

confidence: 67%

A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome

Meetei

Sechi

Wallisch

et al. 2003

Molecular and Cellular Biology

333

344

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Bloom syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one of the complexes, termed BRAFT, also contains five of the Fanconi anemia (FA) complementation group proteins (FA proteins). FA resembles BS in genomic instability and cancer predisposition, but most of its gene products have no known biochemical activity, and the molecular pathogenesis of the disease is poorly understood. BRAFT displays a DNA-unwinding activity, which requires the presence of BLM because complexes isolated from BLM-deficient cells lack such an activity. The complex also contains topoisomerase III␣ and replication protein A, proteins that are known to interact with BLM and could facilitate unwinding of DNA. We show that BLM complexes isolated from an FA cell line have a lower molecular mass. Our study provides the first biochemical characterization of a multiprotein FA complex and suggests a connection between the BLM and FA pathways of genomic maintenance. The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair.

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Section: Resultsmentioning

confidence: 67%

A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome

Meetei

Sechi

Wallisch

et al. 2003

Molecular and Cellular Biology

333

344

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“…BRG1 has been shown to interact with the FANCA protein. 30 Furthermore, BRG1 plays a role in the inducible expression of certain antioxidant genes 43 and in the transcriptional induction of a subset of IFN-inducible genes through interactions with specific transcription factors such as STATs. 44 Our studies, taken together with these reports, suggest that induced recruitment of BRG1 and the FA proteins to the promoters of the antioxidant defense genes by oxidative stress may play a role in the transcriptional induction of these genes.…”

Section: Discussionmentioning

confidence: 99%

The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters

Du¹,

Rani²,

Sipple³

et al. 2012

Blood

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Oxidative stress has been implicated in the pathogenesis of many human diseases including Fanconi anemia (FA), a genetic disorder associated with BM failure and cancer. Here we show that major antioxidant defense genes are downregulated in FA patients, and that gene down-regulation is selectively associated with increased oxidative DNA damage in the promoters of the antioxidant defense genes. Assessment of promoter activity and DNA damage repair kinetics shows that increased initial damage, rather than a reduced repair rate, contributes to the augmented oxidative DNA damage. Mechanistically, FA proteins act in concert with the chromatin-remodeling factor BRG1 to protect the promoters of antioxidant defense genes from oxidative damage. Specifically, BRG1 binds to the promoters of the antioxidant defense genes at steady state. On challenge with oxidative stress, FA proteins are recruited to promoter DNA, which correlates with significant increase in the binding of BRG1 within promoter regions. In addition, oxidative stress-induced FANCD2 ubiquitination is required for the formation of a FA-BRG1-promoter complex. Taken IntroductionOxidative DNA damage is a major source of genomic instability. The most prevalent lesion generated by intracellular reactive oxygen species (ROS) is 8-hydroxydeoxy guanosine (8-oxodG). This lesion causes G:C to T:A transversion mutations and is considered highly mutagenic. 1 There is compelling evidence that 8-oxodG levels are elevated in various human cancers. 2,3 and in animal models of tumors. 4,5 ROS-induced DNA damage can also result in single-or double-strand breaks, which are lethal to the cell if not repaired. 6,7 Although there is a great deal known about DNA repair, we have a limited understanding of the involvement of specific repair pathways in protecting cellular DNA from oxidative damaging agents, particularly ROS. The major pathways involved in DNA repair include repair of single-base damage by the base excision repair (BER) pathway, repair of lesions that distort the DNA helix by the nucleotide excision repair (NER) pathway, and repair of DNA double-strand breaks by homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. [8][9][10] Although the specificity and efficiency of each of these DNA repair pathways is critical to ensure genome stability, the complexity of ROS-induced oxidative DNA damage may require coordination between these different pathways.Cells have developed a battery of defense mechanisms to protect against damage induced by oxidative stress. Antioxidant defense enzymes, including superoxide dismutases, catalase, glutathione peroxidases and peroxiredoxins, as well as nonenzymatic scavengers such as glutathione and carotenoids can directly eliminate ROS. 11 Other cellular enzymes can repair DNA damage induced by ROS. 12 Moreover, ROS can influence the selective activation of oxidative stress-responsive transcription factors.Indeed, the first line of defense against oxidative damage is the induction of stress-response genes, many of whi...

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“…FANCA physically interacts with FANCG and the transcription factor HES1 within the FA core complex (19 -25), which has been found to be localized to chromatin (26,27). FANCA was also found to be involved in psoralen ICL-induced mutagenesis and in spontaneous and UV light-induced base substitution mutagenesis in human cells, implying its involvement in the mutagenic translesion synthesis of DNA damage (28,29).…”

Section: Fanconi Anemia (Fa)mentioning

confidence: 99%

Fanconi Anemia Complementation Group A (FANCA) Protein Has Intrinsic Affinity for Nucleic Acids with Preference for Single-stranded Forms

Yuan

Qian

Zhao

et al. 2012

Journal of Biological Chemistry

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Background:The FANCA (Fanconi anemia complementation group A) gene is mutated in ϳ60% of Fanconi anemia patients, but no biochemical activity has been identified. Results: Purified FANCA binds to nucleic acids of a certain length through its C terminus. Conclusion: FANCA has an intrinsic affinity for nucleic acids with a strong preference for single-stranded forms. Significance: Unveiling the biochemical activity of FANCA is critical for understanding its functions in DNA repair.

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Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex

Cited by 80 publications

References 76 publications

A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome

A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome

The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters

Fanconi Anemia Complementation Group A (FANCA) Protein Has Intrinsic Affinity for Nucleic Acids with Preference for Single-stranded Forms

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