ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

Tan, Winnie; Twest, Sylvie van; Murphy, Vincent J.; Deans, Andrew J.

doi:10.3389/fcell.2020.00002

Cited by 32 publications

(40 citation statements)

References 44 publications

(63 reference statements)

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“…The FANCD2-FANCI heterodimer, frequently called the central complex, is recruited to the stalled fork, where FANCI is tri-phosphorylated by the ATR-kinase [ 15 ], stimulating the FA core complex mediated monoubiquitination of both FANCI and FANCD2. The tri-phosphorylation of FANCI also inhibits the deubiquitinase activity of the USP1-UAF1 complex over the ID2 complex until ICL repair and replication are completed [ 15 ]. The ubiquitinated ID2 complex protects the replication forks and regulates the activity of the proteins involved in the processing of the ICL, enabling the recruitment of the proteins of the fourth module.…”

Section: Double Strand Breaks Are At the Center Of Chromosome Abermentioning

confidence: 99%

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

García-de-Teresa

Rodríguez

Frı́as

2020

Genes

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Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA.

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Section: Double Strand Breaks Are At the Center Of Chromosome Abermentioning

confidence: 99%

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

García-de-Teresa

Rodríguez

Frı́as

2020

Genes

View full text Add to dashboard Cite

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“…The FANCD2-FANCI heterodimer, frequently called the central complex, is recruited to the stalled fork, where FANCI is tri-phosphorylated by the ATRkinase [15], stimulating the FA core complex mediated monoubiquitination of both FANCI and FANCD2. The tri-phosphorylation of FANCI also inhibits the deubiquitinase activity of the USP1-UAF1 complex over the ID2 complex until ICL repair and replication are completed [15]. The ubiquitinated ID2 complex protects the replication forks and regulates the activity of the proteins involved in the processing of the ICL, enabling the recruitment of the proteins of the fourth module.…”

Section: Involvement Of Fa/brca Pathway In Dna Repairmentioning

confidence: 99%

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

García-de-Teresa

Rodríguez

Frı́as

2020

Preprint

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Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, that cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired, and accumulation of toxic DNA double strand breaks occurs. In order to repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, that may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA and their segregation during cell division are the origin of subsequent aberrations like translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, that results in tissue attrition, selection of malignant clones and cancer onset. Moreover, the effect of the FA/BRCA pathway in germinal cells, evidenced by infertility in patients with FA attests of chromosomal instability and cell death also occurring in the germinal compartment.

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“…In addition, the β-propeller domain of UAF1 interacts with a loop connecting the NTD and HD of FANCI (FANCI 547-576 ), the phosphorylation of which inhibits deubiquitination by USP1-UAF1 28,29 ( Fig. 3a).…”

Section: Uaf1 and Fanci Form A Scaffold For Deubiquitinationmentioning

confidence: 99%

“…Furthermore, FANCI buries a substantial surface of FANCD2's ubiquitin 15,16 , which shields it from several deubiquitinases but not USP1-UAF1 in vitro 18 . Instead, FANCI phosphorylation is reported to impede USP1-UAF1 activity 28,29 ; the underlying mechanism of this regulation remains unclear. Recently, biochemical work has shown that the NTE of USP1 is critical for specific removal of FANCD2's ubiquitin 20 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis of FANCD2 deubiquitination by USP1-UAF1

Rennie

Arkinson

Chaugule

et al. 2020

Preprint

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Ubiquitin-Specific Protease 1 (USP1), together with the cofactor UAF1, acts during DNA repair processes to specifically to remove mono-ubiquitin signals. The mono-ubiquitinated FANCI-FANCD2 heterodimer is one such substrate and is involved in the repair of DNA interstrand crosslinks via the Fanconi Anemia pathway. Here we determine structures of human USP1-UAF1 with and without ubiquitin, and bound to mono-ubiquitinated FANCI-FANCD2 substrate. Crystal structures of USP1-UAF1 reveal plasticity in USP1 and key differences to USP12-UAF1 and USP46-UAF1. A cryoEM reconstruction of USP1-UAF1 in complex mono-ubiquitinated FANCI-FANCD2, highlights a highly orchestrated deubiquitination process with USP1-UAF1 driving conformational changes in the substrate. An extensive interface between UAF1 and FANCI, confirmed by mutagenesis and biochemical assays, provides a molecular explanation for their requirement despite neither being directly involved in catalysis. Overall, our data provide molecular details of USP1-UAF1 regulation and substrate recognition.

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ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

Cited by 32 publications

References 44 publications

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Structural basis of FANCD2 deubiquitination by USP1-UAF1

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