Monoubiquitination by the human Fanconi anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays

Tan, Winnie; Twest, Sylvie van; Leis, Andrew; Bythell-Douglas, Rohan; Murphy, Vincent J.; Sharp, Michael F.; Parker, Michael W.; Crismani, Wayne; Deans, Andrew J.

doi:10.7554/elife.54128

Cited by 61 publications

(64 citation statements)

References 75 publications

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“…Metaphorically, this rotation closes the trough observed in apo-FANCI–FANCD2, clamping the complex on DNA. This conformational change significantly decreases the off-rate of FANCI–FANCD2 to dsDNA [ 21 , 24 ], which is the central event for DNA repair activation. The main finding of the present study is that the ubiquitin acts as a wedge to stabilize the FANCI–FANCD2 closed conformation on DNA [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Four concurrent studies also demonstrated a requirement for FANCD2 Ub but not FANCI Ub in DNA clamping, for human, chicken and Xenopus homologs [ 21 , 24 , 25 , 33 ]. The cryo-EM structures of di-monoubiquitinated human FANCI–FANCD2 (FANCI Ub –FANCD2 Ub , PDB: 6VAE , 3.8 Å) reveals why this is the case ( Figure 2 B) [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…This precluded FANCI–FANCD2 binding by other proteins with ubiquitin-binding domains (such as UBZ and CUE domains) [ 34–36 ]. Furthermore, biochemical pulldown of monoubiquitinated FANCI–FANCD2 with DNA repair proteins that contain ubiquitin-binding domains showed that monoubiquitination did not alter interaction of FANCI–FANCD2 with the DNA repair proteins [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…This is a possibility but has not yet been observed in any of the studies described above. Further, we recently demonstrated that purified FANCI Ub –FANCD2 Ub is not bound preferentially by any of the DNA repair proteins that had been hypothesized to be important in the FA pathway [ 24 ]. This includes nucleases such as FAN1 and SLX4 [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…We propose that DNA clamping protects the DNA or controls its branch migration, by forming arrays on dechromatinized DNA at stalled replication forks. Evidence for this comes from our striking observation of long filamentous arrays of FANCI Ub –FANCD2 Ub when it is ubiquitinated and purified together with long dsDNA (plasmid length compared with 20–30 bp in the cryo-EM structures) and observed under the electron microscope ( Figure 3 C,D) [ 24 ]. This was unexpected.…”

Section: Introductionmentioning

confidence: 99%

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Structural insight into FANCI–FANCD2 monoubiquitination

Tan

Deans

2020

Essays in Biochemistry

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The Fanconi anemia (FA) pathway coordinates a faithful repair mechanism for DNA damage that blocks DNA replication, such as interstrand cross-links. A key step in the FA pathway is the conjugation of ubiquitin on to FANCD2 and FANCI, which is facilitated by a large E3 ubiquitin ligase complex called the FA core complex. Mutations in FANCD2, FANCI or FA core complex components cause the FA bone marrow failure syndrome. Despite the importance of these proteins to DNA repair and human disease, our molecular understanding of the FA pathway has been limited due to a deficit in structural studies. With the recent development in cryo-electron microscopy (EM), significant advances have been made in structural characterization of these proteins in the last 6 months. These structures, combined with new biochemical studies, now provide a more detailed understanding of how FANCD2 and FANCI are monoubiquitinated and how DNA repair may occur. In this review, we summarize these recent advances in the structural and molecular understanding of these key components in the FA pathway, compare the activation steps of FANCD2 and FANCI monoubiquitination and suggest molecular steps that are likely to be involved in regulating its activity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural insight into FANCI–FANCD2 monoubiquitination

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Deans

2020

Essays in Biochemistry

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DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies

Rominiyi

Collis

2021

Molecular Oncology

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Glioblastoma is the most frequently diagnosed type of primary brain tumour in adults.These aggressive tumours are characterised by inherent treatment resistance and disease progression, contributing to ~190,000 brain-tumour related deaths globally each year. Current therapeutic interventions consist of surgical resection followed by radiotherapy and temozolomide chemotherapy, but average survival is typically around 1 year, with less than 10% of patients surviving more than 5 years. Recently, a fourth treatment modality of intermediate-frequency low-intensity electric fields [called tumourtreating fields ( TTFields)] was clinically approved for glioblastoma in some countries after it was found to increase median overall survival rates by ~5 months in a phase III randomised clinical trial. However, beyond these treatments, attempts to establish more effective therapies have yielded little improvement in survival for patients over the last 50 years. This is in contrast to many other types of cancer and highlights glioblastoma as a recognised tumour of unmet clinical need. Previous work has revealed that glioblastomas contain stem-cell-like subpopulations that exhibit heightened expression of DNA damage

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The emergence of a unified mechanism in the Fanconi anemia pathway

Guo

2021

GENOME INSTAB. DIS.

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Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, developmental abnormalities and a predisposition to cancer, particularly acute myeloid leukemia. So far, 22 FA genes (FANCA-W) have been identified. Germline inactivation of any one of the 22 currently known FA genes causes FA. Proteins encoded by FA genes are involved in the Fanconi anemia pathway, which repairs DNA interstrand crosslinks (ICLs). The main function of the FA pathway in repairing ICLs has been extensively studied. In addition, several lines of evidence indicate that the FA pathway has crucial roles in genome maintenance upon replication stress, and is involved in common fragile sites, R-loops, and mitotic DNA synthesis. Recently, we found that all the functions of the FA pathway are possibly derived from one unified mechanism, namely that FA proteins play a role in the cleavage-coupled break-induced replication pathway to restart stalled replication forks. In the review, we summarize our current understanding of the functions of the FA pathway, and review our knowledge of the potential endogenous pathogenic factors that contribute to FA.

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Monoubiquitination by the human Fanconi anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays

Cited by 61 publications

References 75 publications

Structural insight into FANCI–FANCD2 monoubiquitination

Structural insight into FANCI–FANCD2 monoubiquitination

DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies

The emergence of a unified mechanism in the Fanconi anemia pathway

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