Fanconi anemia (FA) and crosslinker sensitivity: Re‐appraising the origins of FA definition

Pagano, Giovanni; d’Ischia, Marco; Pallardó, Federico V.

doi:10.1002/pbc.25452

Cited by 12 publications

(9 citation statements)

References 84 publications

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“…Alternative Functions for FA Proteins Are Crucial for Understanding Disease Pathogenesis. FANCI's function in the NO is one of three recent observations that indicate FA proteins have roles in processes other than DNA repair (33,76,77). Sumpter et al (76) discovered a cytoplasmic role for the FANCC protein in selective autophagy of viruses (virophagy) and mitochondria (mitophagy).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, such a connection between FA and cellular pathways outside DNA repair was first hypothesized over 10 y ago (3). It was recently argued that clinical insight and management of FA would be better served by a "shared axiom" incorporating the DNA repair functions of FA proteins with their other functions (77). Our work and that of Johnston et al Densitometric quantitation of Western blots from three biological replicates for nucleoplasmic and nucleolar FANCI (A) and FANCD2 (B) relative to WCE from cells treated with 2 mM HU for 24 h. All quantitations were performed using the same Western blots as in Fig.…”

Section: Discussionmentioning

confidence: 99%

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Fanconi anemia protein FANCI functions in ribosome biogenesis

Sondalle

Longerich

Ogawa

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Fanconi anemia (FA) is a disease of DNA repair characterized by bone marrow failure and a reduced ability to remove DNA interstrand cross-links. Here, we provide evidence that the FA protein FANCI also functions in ribosome biogenesis, the process of making ribosomes that initiates in the nucleolus. We show that FANCI localizes to the nucleolus and is functionally and physically tied to the transcription of pre-ribosomal RNA (pre-rRNA) and to large ribosomal subunit (LSU) pre-rRNA processing independent of FANCD2. While FANCI is known to be monoubiquitinated when activated for DNA repair, we find that it is predominantly in the deubiquitinated state in the nucleolus, requiring the nucleoplasmic deubiquitinase (DUB) USP1 and the nucleolar DUB USP36. Our model suggests a possible dual pathophysiology for FA that includes defects in DNA repair and in ribosome biogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fanconi anemia protein FANCI functions in ribosome biogenesis

Sondalle

Longerich

Ogawa

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Because FA proteins mediate DNA interstrand crosslink repair, cells from affected patients show hypersensitivity to crosslinking agents such as Mitomycin C (MMC), Diepoxybutane (DEB) and Cyclophosphamide. The increased amount of chromosome breaks observed in FA cells upon treatment with DEB is used as a diagnostic tool to confirm that an individual does indeed harbor a mutation within one of the Fanconi anemia genes [ 10 ]. Consistent with the association of genome integrity with carcinogenesis, FA patients suffer from myeloid leukemias, liver tumors, head and neck carcinomas, and gynecologic malignancies more frequently and at a younger age than the general population [ 11 , 12 ].…”

Section: Genomic Instability and Fanconi Anemiamentioning

confidence: 99%

Maintenance of genome stability by Fanconi anemia proteins

et al. 2017

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Persistent dysregulation of the DNA damage response and repair in cells causes genomic instability. The resulting genetic changes permit alterations in growth and proliferation observed in virtually all cancers. However, an unstable genome can serve as a double-edged sword by providing survival advantages in the ability to evade checkpoint signaling, but also creating vulnerabilities through dependency on alternative genomic maintenance factors. The Fanconi anemia pathway comprises an intricate network of DNA damage signaling and repair that are critical for protection against genomic instability. The importance of this pathway is underlined by the severity of the cancer predisposing syndrome Fanconi anemia which can be caused by biallelic mutations in any one of the 21 genes known thus far. This review delineates the roles of the Fanconi anemia pathway and the molecular actions of Fanconi anemia proteins in confronting replicative, oxidative, and mitotic stress.

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“…The field of FA cancer research progresses rapidly, and there are FA cases yet to be defined [ 39 ]. This may raise an issue of how to accurately define the wild type status of the FA pathway.…”

Section: Discussionmentioning

confidence: 99%

Mutated Fanconi anemia pathway in non-Fanconi anemia cancers

et al. 2015

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An extremely high cancer incidence and the hypersensitivity to DNA crosslinking agents associated with Fanconi Anemia (FA) have marked it to be a unique genetic model system to study human cancer etiology and treatment, which has emerged an intense area of investigation in cancer research. However, there is limited information about the relationship between the mutated FA pathway and the cancer development or/and treatment in patients without FA. Here we analyzed the mutation rates of the seventeen FA genes in 68 DNA sequence datasets. We found that the FA pathway is frequently mutated across a variety of human cancers, with a rate mostly in the range of 15 to 35 % in human lung, brain, bladder, ovarian, breast cancers, or others. Furthermore, we found a statistically significant correlation (p < 0.05) between the mutated FA pathway and the development of human bladder cancer that we only further analyzed. Together, our study demonstrates a previously unknown fact that the mutated FA pathway frequently occurs during the development of non-FA human cancers, holding profound implications directly in advancing our understanding of human tumorigenesis as well as tumor sensitivity/resistance to crosslinking drug-relevant chemotherapy.

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Fanconi anemia (FA) and crosslinker sensitivity: Re‐appraising the origins of FA definition

Cited by 12 publications

References 84 publications

Fanconi anemia protein FANCI functions in ribosome biogenesis

Fanconi anemia protein FANCI functions in ribosome biogenesis

Maintenance of genome stability by Fanconi anemia proteins

Mutated Fanconi anemia pathway in non-Fanconi anemia cancers

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