Fanconi Anemia (Cross)linked to DNA Repair

Niedernhofer, Laura J.; Lalai, Astrid S.; Hoeijmakers, Jan H.J.

doi:10.1016/j.cell.2005.12.009

Cited by 267 publications

(258 citation statements)

References 39 publications

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“…Current modelspredict that DNA integrity is not restored without cleaving the 3´ and 5´ sequences flanking the lesion. Several nucleases contribute to ICLR, such as XPF-ERCC1, MUS81-EME1, SLX1, SNM1A, and SNM1B [43][44][45]. However, the lack of FA patients with mutations in the genes encoding these nucleases hindered the identification of the main FA/BRCA pathway nuclease.…”

Section: Fa Genes (Fanca B C D1 D2 E F G I J L N P Q) Fmentioning

confidence: 99%

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Bogliolo

Surrallés

2015

Current Opinion in Genetics & Development

162

167

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Section: Fa Genes (Fanca B C D1 D2 E F G I J L N P Q) Fmentioning

confidence: 99%

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Bogliolo

Surrallés

2015

Current Opinion in Genetics & Development

162

167

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“…Several models for mammalian ICL repair have been proposed (2,(5)(6)(7). The first critical step for repairing ICLs in any given model is to release the ICL from one of the strands by making two incisions that bracket an ICL (unhooking the ICL).…”

Section: Dna Interstrand Cross-links (Icls)mentioning

confidence: 99%

Processing of a Psoralen DNA Interstrand Cross-link by XPF-ERCC1 Complex in Vitro

Fisher

Bessho

2008

Journal of Biological Chemistry

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The processing of stalled forks caused by DNA interstrand cross-links (ICLs) has been proposed to be an important step in initiating mammalian ICL repair. To investigate a role of the XPF-ERCC1 complex in this process, we designed a model substrate DNA with a single psoralen ICL at a three-way junction (Y-shaped DNA), which mimics a stalled fork structure. We found that the XPF-ERCC1 complex makes an incision 5 to a psoralen lesion on Y-shaped DNA in a damage-dependent manner. Furthermore, the XPF-ERCC1 complex generates an ICLspecific incision on the 3-side of an ICL. The ICL-specific 3-incision, along with the 5-incision, on the cross-linked Y-shaped DNA resulted in the separation of the two cross-linked strands (the unhooking of the ICL) and the induction of a double strand break near the cross-linked site. These results implicate the XPF-ERCC1 complex in initiating ICL repair by unhooking the ICL, which simultaneously induces a double strand break at a stalled fork. DNA interstrand cross-links (ICLs)2 are formed as a result of DNA damage to each strand of the duplex. These lesions are located one or two nucleotides apart on the opposite strands and covalently link them, blocking DNA replication and transcription (1-3). Therefore, ICLs are considered to be the most cytotoxic DNA lesion (2-4).Several models for mammalian ICL repair have been proposed (2, 5-7). The first critical step for repairing ICLs in any given model is to release the ICL from one of the strands by making two incisions that bracket an ICL (unhooking the ICL). The unhooking of ICLs permits strand separation. In Escherichia coli and yeast, nucleotide excision repair (NER) makes dual incisions bracketing the ICL on one of the cross-linked strands to unhook ICLs (2, 3). Interestingly, NER is dispensable in mammalian ICL repair (5,8). In contrast to NER-defective mutants in E. coli and yeast, the NER-defective mammalian cells (except for ERCC-1 and ERCC-4 cells) are only moderately sensitive to DNA cross-linking agents such as mitomycin C (MMC) (8 -11). Moreover, biochemical studies demonstrated that the dual incisions by mammalian NER do not "unhook" ICLs (12, 13). Therefore, mammalian cells evidently have a unique mechanism(s) to initiate ICL repair.Notably, double strand break (DSB) repair-defective mutant cells, including those deficient in Rad51 paralogs or BRCA2, are hypersensitive to DNA cross-linking agents such as MMC (10). It has also been reported that ICLs in the mammalian genome are removed during S-phase and the DNA replication-mediated formation of a DSB is the key intermediate in ICL repair in mammalian cells (1,8,14,15). These data indicate that mammalian ICL repair goes through three critical processes: the formation of DNA replication-mediated DSBs, unhooking of the ICLs (separation of the two linked strands), and repair of the DSBs (restoration of the collapsed replication fork). It is unknown whether the formation of DSBs precedes the unhooking reaction. When the DNA replication complex encounters an ICL, the strand separat...

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“…Deleterious mutations in genes encoding DNA-repair proteins can lead to several different diseases, many of which share common features such as formation of unusual chromosomal structures in affected cells and cancer predisposition in afflicted individuals. Fanconi anemia (FA), an autosomal recessive disease caused by mutations in any of 15 genes involved in the repair of DNA interstrand crosslinks (ICLs), is an example of such a disease (1)(2)(3). FA patients suffer developmental abnormalities, progressive bone marrow failure, and a high incidence of cancer.…”

mentioning

confidence: 99%

Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome

Hoadley

Xue

Chen

et al. 2012

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

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The RMI subcomplex (RMI1/RMI2) functions with the BLM helicase and topoisomerase IIIα in a complex called the "dissolvasome," which separates double-Holliday junction DNA structures that can arise during DNA repair. This activity suppresses potentially harmful sister chromatid exchange (SCE) events in wild-type cells but not in cells derived from Bloom syndrome patients with inactivating BLM mutations. The RMI subcomplex also associates with FANCM, a component of the Fanconi anemia (FA) core complex that is important for repair of stalled DNA replication forks. The RMI/ FANCM interface appears to help coordinate dissolvasome and FA core complex activities, but its precise role remains poorly understood. Here, we define the structure of the RMI/FANCM interface and investigate its roles in coordinating cellular DNA-repair activities. The X-ray crystal structure of the RMI core complex bound to a well-conserved peptide from FANCM shows that FANCM binds to both RMI proteins through a hydrophobic "knobsinto-holes" packing arrangement. The RMI/FANCM interface is shown to be critical for interaction between the components of the dissolvasome and the FA core complex. FANCM variants that substitute alanine for key interface residues strongly destabilize the complex in solution and lead to increased SCE levels in cells that are similar to those observed in blm-or fancm-deficient cells. This study provides a molecular view of the RMI/FANCM complex and highlights a key interface utilized in coordinating the activities of two critical eukaryotic DNA-damage repair machines.

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Fanconi Anemia (Cross)linked to DNA Repair

Cited by 267 publications

References 39 publications

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Processing of a Psoralen DNA Interstrand Cross-link by XPF-ERCC1 Complex in Vitro

Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome

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