Damage-Resistant DNA Synthesis in Fanconi Anemia Cells Treated with a DNA Cross-Linking Agent

Centurion, Santiago A.; Kuo, Hon-Reen; Lambert, W. Clark

doi:10.1006/excr.2000.4995

Cited by 40 publications

(24 citation statements)

References 29 publications

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“…Using mutant cDNA constructs of human FANCD2, it was shown that this modification was necessary for the arrest of DNA synthesis after DNA damage, an ATM-dependent function (Taniguchi et al 2002b). In addition, others have reported a defect in Sphase arrest in response to PUVA in multiple FA cell lines (Centurion et al 2000;Sala-Trepat et al 2000). These findings prompted the investigation of the status of the checkpoint in primary Fancd2 mutant MEFs.…”

Section: Primary Fancd2 Mutant Fibroblasts Have An Intact Atm-dependementioning

confidence: 97%

Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

Houghtaling¹,

Timmers²,

Noll³

et al. 2003

Genes Dev.

269

298

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Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA damage, bone marrow failure, congenital defects, and cancer. To further investigate the in vivo function of the FA pathway, mice with a targeted deletion in the distally acting FA gene Fancd2 were created. Similar to human FA patients and other FA mouse models, Fancd2 mutant mice exhibited cellular sensitivity to DNA interstrand cross-links and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However, Fancd2 mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These include microphthalmia, perinatal lethality, and epithelial cancers, similar to mice with Brca2/Fancd1 hypomorphic mutations. These additional phenotypes were not caused by defects in the ATM-mediated S-phase checkpoint, which was intact in primary Fancd2 mutant fibroblasts. The phenotypic overlap between Fancd2-null and Brca2/Fancd1 hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability.[Keywords: Fanconi anemia; cancer; Fancd2; Brca2; DNA repair; chromosome pairing] Supplemental material is available at http://www.genesdev.org.

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Section: Primary Fancd2 Mutant Fibroblasts Have An Intact Atm-dependementioning

confidence: 97%

Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

Houghtaling¹,

Timmers²,

Noll³

et al. 2003

Genes Dev.

269

298

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“…It also functions to stop the firing of further DNA replication origins, preventing the formation of new replication forks until the existing damage has been repaired (Bartek et al 2004). A role for the FA pathway in the replication checkpoint is supported by the observations that FANCD2 monoubiquitination is dependent on ATR activation and that constituents of complex 1 (the E3 ligase complex) and FANCD2 have both been shown to be required for S-phase cell cycle arrest following cross-link damage (Centurion et al 2000;Sala-Trepat et al 2000;Pichierri and Rosselli 2004).…”

Section: Cell Cycle Regulationmentioning

confidence: 99%

“…Indeed, this consistent observation has been proposed as a diagnostic test for FA (Miglierina et al 1991). One hypothesis to explain this phenotype has been that FA cells fail to arrest in S phase due to DNA damage and accumulate at the G2/M damage checkpoint (Centurion et al 2000;Sala-Trepat et al 2000). Other investigators have proposed that FA cells arrest in late S phase due to a failure to remove DNA cross-links (Akkari et al 2001).…”

Section: Cell Cycle Regulationmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

362

345

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Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.

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“…6C). Inefficient S-phase checkpoints in response to ICL in human FA cells (7,42) might be relevant to this phenotype.…”

Section: Ig V Gene Conversion Is Associated With a Decrease In Nontemmentioning

confidence: 99%

Fanconi Anemia Protein FANCD2 Promotes Immunoglobulin Gene Conversion and DNA Repair through a Mechanism Related to Homologous Recombination

Yamamoto

Hirano

Ishiai

et al. 2005

Molecular and Cellular Biology

127

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Recent studies show overlap between Fanconi anemia (FA) proteins and those involved in DNA repair mediated by homologous recombination (HR). However, the mechanism by which FA proteins affect HR is unclear. FA proteins (FancA/C/E/F/G/L) form a multiprotein complex, which is responsible for DNA damageinduced FancD2 monoubiquitination, a key event for cellular resistance to DNA damage. Here, we show that FANCD2-disrupted DT40 chicken B-cell line is defective in HR-mediated DNA double-strand break (DSB) repair, as well as gene conversion at the immunoglobulin light-chain locus, an event also mediated by HR. Gene conversions occurring in mutant cells were associated with decreased nontemplated mutations. In contrast to these defects, we also found increased spontaneous sister chromatid exchange (SCE) and intact Rad51 foci formation after DNA damage. Thus, we propose that FancD2 promotes a subpathway of HR that normally mediates gene conversion by a mechanism that avoids crossing over and hence SCEs.

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Damage-Resistant DNA Synthesis in Fanconi Anemia Cells Treated with a DNA Cross-Linking Agent

Cited by 40 publications

References 29 publications

Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Fanconi Anemia Protein FANCD2 Promotes Immunoglobulin Gene Conversion and DNA Repair through a Mechanism Related to Homologous Recombination

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