The Fanconi road to cancer: Figure 1.

D’Andrea, Alan D.

doi:10.1101/gad.1128303

Cited by 91 publications

(46 citation statements)

References 32 publications

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“…Furthermore, reduced Hus1 expression did not affect the kinetics of tumor development in p53 ϩ/Ϫ or p53 Ϫ/Ϫ mice or significantly change the spectrum of tumors arising in these animals. Several other mouse models featuring defects in cell cycle checkpoints and/or DNA repair similarly do not show increased cancer incidence (1,13,47,52,66). These data contribute to the emerging picture that a particular type and level of genomic instability may be critical to tumor development (9).…”

Section: Vol 27 2007mentioning

confidence: 84%

“…These findings are in accord with current models suggesting that replication stress in checkpoint-defective cells results in replication fork collapse (5 cells accumulated not only gaps and breaks but also chromatid interchanges at high frequency. This phenotype is somewhat reminiscent of that observed for Fanconi anemia cells following treatment with mitomycin C, which also involves high-frequency radial chromosome formation (13). Genotoxin-induced chromatid interchanges are believed to reflect a failure of DNA repair by homologous recombination and increased use of error-prone pathways such as nonhomologous end joining and single-strand annealing.…”

Section: Hus1 Neo/⌬1mentioning

confidence: 88%

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Genome Maintenance Defects in Cultured Cells and Mice following Partial Inactivation of the Essential Cell Cycle Checkpoint Gene Hus1

Levitt

Zhu

Cassano

et al. 2007

Molecular and Cellular Biology

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Cell cycle checkpoints are evolutionarily conserved signaling pathways that uphold genomic integrity. Complete inactivation of the mouse checkpoint gene Hus1 results in chromosomal instability, genotoxin hypersensitivity, and embryonic lethality. To determine the functional consequences of partial Hus1 impairment, we generated an allelic series in which Hus1 expression was incrementally reduced by combining a hypomorphic The ability to accurately duplicate the genome and correctly segregate damage-free chromosomes to daughter cells is crucial to the health and longevity of all organisms. To ensure the fidelity of these processes, cells respond to genome damage by arresting the cell cycle, stabilizing replication forks, and inducing DNA repair. Cell cycle checkpoint pathways mediate these DNA damage responses and additionally can induce apoptosis if the damage is beyond repair. By preventing the accumulation of mutations that drives carcinogenesis, checkpoints can be important tumor suppressor mechanisms (3,21,27).Replication inhibitors and bulky DNA lesions activate a checkpoint pathway headed by the phosphatidylinositol kinase-like protein kinase Atr. Stalling of replication forks or processing of DNA lesions causes accumulation of singlestranded DNA that becomes coated with replication protein A (RPA) and attracts Atr in association with its binding partner Atrip (12). Atr then transmits the checkpoint signal by phosphorylating Chk1, Brca1, and other targets, which in turn regulate the cell cycle, replication, and repair machineries. Efficient DNA damage signaling through Atr also requires several accessory factors, including TopBP1/Cut5, Claspin, and the Rad9-Rad1-Hus1 (9-1-1) complex (44).With predicted structural similarity to proliferating cell nuclear antigen (PCNA), the 9-1-1 complex is believed to function as a checkpoint sliding clamp and molecular scaffold (57). Loading of the 9-1-1 trimer onto chromatin is stimulated by genotoxic stress and is mediated by a clamp loader composed of Rad17 and associated replication factor C subunits (8,41,67). Once on chromatin, the 9-1-1 complex participates in DNA damage signaling, promoting phosphorylation of Atr substrates such as Chk1, Rad17, and Rad9 itself (2,40,65,67). Signaling defects in cells lacking 9-1-1 components are associated with failure of an S-phase checkpoint that represses late origin firing in response to DNA damage (2, 40, 64). The mammalian 9-1-1 complex also directly associates with a number of DNA repair proteins, including factors involved in base excision repair (10,20,46,48,55,58,59) and translesion DNA synthesis (26, 42), and additionally is required for homologous recombinational repair (37, 61) as well as telomere maintenance (19,37). Given these key roles in checkpoint signaling and DNA repair, it is not surprising that cells defective for 9-1-1 function are hypersensitive to a wide variety of genotoxins, including replication inhibitors and DNA damaging agents (23,28,40,60,61,63,64).The mammalian 9-1-1 complex not only responds to ex...

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Section: Vol 27 2007mentioning

confidence: 84%

Section: Hus1 Neo/⌬1mentioning

confidence: 88%

Genome Maintenance Defects in Cultured Cells and Mice following Partial Inactivation of the Essential Cell Cycle Checkpoint Gene Hus1

Levitt

Zhu

Cassano

et al. 2007

Molecular and Cellular Biology

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“…Defects in a variety of DNA repair pathways result in diseases characterized by a range of distinct phenotypes. For example, defects in DNA helicases (for example, Bloom syndrome) can result in dwarfism and increased sister-chromatid exchange, defects in the repair of DNA crosslinks (Fanconi anemia) is associated with diverse congenital abnormalities and bone marrow failure, while defects in the repair of UV damage (for example, xeroderma pigmentosum) can lead to sun-induced skin and eye lesions, and all of these DNA repair syndromes predispose to cancer (van Brabant et al, 2000;Hoeijmakers, 2001;D'Andrea, 2003;Cleaver, 2005). Human syndromes also result from defective responses to DNA double-strand breaks (DSBs), such as ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) that show striking effects in the nervous and immune systems and exhibit cancer predisposition (McKinnon and Caldecott, 2007).…”

Section: Introductionmentioning

confidence: 99%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

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“…Accordingly, mutants of the RAD52 group are sensitive to genotoxic agents, bear a strong mutator phenotype, and exhibit severe meiotic abnormalities (2). In mammals, a deficiency in HR causes cell inviability and can lead to the cancer phenotype (4,5).…”

mentioning

confidence: 99%

Molecular Anatomy of the Recombination Mediator Function of Saccharomyces cerevisiae Rad52

Seong

Sehorn

Plate

et al. 2008

Journal of Biological Chemistry

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A helical filament of Rad51 on single-strand DNA (ssDNA), called the presynaptic filament, catalyzes DNA joint formation during homologous recombination. Rad52 facilitates presynaptic filament assembly, and this recombination mediator activity is thought to rely on the interactions of Rad52 with Rad51, the ssDNA-binding protein RPA, and ssDNA. The N-terminal region of Rad52, which has DNA binding activity and an oligomeric structure, is thought to be crucial for mediator activity and recombination. Unexpectedly, we find that the C-terminal region of Rad52 also harbors a DNA binding function. Importantly, the Rad52 C-terminal portion alone can promote Rad51 presynaptic filament assembly. The middle portion of Rad52 associates with DNAbound RPA and contributes to the recombination mediator activity. Accordingly, expression of a protein species that harbors the middle and C-terminal regions of Rad52 in the rad52 ⌬327 background enhances the association of Rad51 protein with a HO-made DNA double-strand break and partially complements the methylmethane sulfonate sensitivity of the mutant cells. Our results provide a mechanistic framework for rationalizing the multi-faceted role of Rad52 in recombination and DNA repair.

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The Fanconi road to cancer: Figure 1.

Cited by 91 publications

References 32 publications

Genome Maintenance Defects in Cultured Cells and Mice following Partial Inactivation of the Essential Cell Cycle Checkpoint Gene Hus1

Genome Maintenance Defects in Cultured Cells and Mice following Partial Inactivation of the Essential Cell Cycle Checkpoint Gene Hus1

DNA double-strand break repair and development

Molecular Anatomy of the Recombination Mediator Function of Saccharomyces cerevisiae Rad52

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