Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance

Cabelof, Diane C.

doi:10.1007/s00018-011-0839-7

Cited by 19 publications

(14 citation statements)

References 77 publications

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“…The implications for DNA repair and DDR pathways in this context merits closer attention. There already exists tantalizing evidence to suggest that these pathways are sensitive to gene dosage (O'Driscoll 2008;Cabelof 2012;Depienne et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Diseases Associated with Defective Responses to DNA Damage

O’Driscoll

2012

Cold Spring Harbor Perspectives in Biology

106

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Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

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Section: Discussionmentioning

confidence: 99%

Diseases Associated with Defective Responses to DNA Damage

O’Driscoll

2012

Cold Spring Harbor Perspectives in Biology

106

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“…In addition, APE1 heterozygosity in mice results in increased sensitivity to oxidative stress, reduced survival of pups and embryos, increased incidence of papillary adenocarcinoma and lymphoma, and elevated mutagenesis [15]–[17]. While sufficient depletion of APE1 in cells can lead to apoptosis [18], [19], inhibition or downregulation of this protein can sensitize cells to various DNA-damaging agents [20].…”

Section: Introductionmentioning

confidence: 99%

Identification and Quantification of DNA Repair Protein Apurinic/Apyrimidinic Endonuclease 1 (APE1) in Human Cells by Liquid Chromatography/Isotope-Dilution Tandem Mass Spectrometry

et al. 2013

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Unless repaired, DNA damage can drive mutagenesis or cell death. DNA repair proteins may therefore be used as biomarkers in disease etiology or therapeutic response prediction. Thus, the accurate determination of DNA repair protein expression and genotype is of fundamental importance. Among DNA repair proteins involved in base excision repair, apurinic/apyrimidinic endonuclease 1 (APE1) is the major endonuclease in mammals and plays important roles in transcriptional regulation and modulating stress responses. Here, we present a novel approach involving LC-MS/MS with isotope-dilution to positively identify and accurately quantify APE1 in human cells and mouse tissue. A completely 15N-labeled full-length human APE1 was produced and used as an internal standard. Fourteen tryptic peptides of both human APE1 (hAPE1) and 15N-labeled hAPE1 were identified following trypsin digestion. These peptides matched the theoretical peptides expected from trypsin digestion and provided a statistically significant protein score that would unequivocally identify hAPE1. Using the developed methodology, APE1 was positively identified and quantified in nuclear and cytoplasmic extracts of multiple human cell lines and mouse liver using selected-reaction monitoring of typical mass transitions of the tryptic peptides. We also show that the methodology can be applied to the identification of hAPE1 variants found in the human population. The results describe a novel approach for the accurate measurement of wild-type and variant forms of hAPE1 in vivo, and ultimately for defining the role of this protein in disease development and treatment responses.

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“…Here folate depletion significantly reduced the total number of ACF in response to DMH. DNA repair deficiencies are modifiers of penetrance [89], but typically in the opposite direction observed in the Ventrella-Lucente paper. However, another study looking at the APC min⁡ mouse likewise found that a DNA repair mutant (Ku70) ameliorated the impact of the APC mutation on tumorigenesis [90].…”

Section: Folate Depletion and Colorectal Carcinogenesismentioning

confidence: 99%

Folate and Colorectal Cancer in Rodents: A Model of DNA Repair Deficiency

Rosati

Cabelof

2012

Journal of Oncology

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Fortification of grains has resulted in a positive public health outcome vis-a-vis reduced incidence of neural tube defects. Whether folate has a correspondingly beneficial effect on other disease outcomes is less clear. A role for dietary folate in the prevention of colorectal cancer has been established through epidemiological data. Experimental data aiming to further elucidate this relationship has been somewhat equivocal. Studies report that folate depletion increases DNA damage, mutagenesis, and chromosomal instability, all suggesting inhibited DNA repair. While these data connecting folate depletion and inhibition of DNA repair are convincing, we also present data demonstrating that genetic inhibition of DNA repair is protective in the development of preneoplastic colon lesions, both when folate is depleted and when it is not. The purpose of this paper is to (1) give an overview of the data demonstrating a DNA repair defect in response to folate depletion, and (2) critically compare and contrast the experimental designs utilized in folate/colorectal cancer research and the corresponding impact on tissue folate status and critical colorectal cancer endpoints. Our analysis suggests that there is still an important need for a comprehensive evaluation of the impact of differential dietary prescriptions on blood and tissue folate status.

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Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance

Cited by 19 publications

References 77 publications

Diseases Associated with Defective Responses to DNA Damage

Diseases Associated with Defective Responses to DNA Damage

Identification and Quantification of DNA Repair Protein Apurinic/Apyrimidinic Endonuclease 1 (APE1) in Human Cells by Liquid Chromatography/Isotope-Dilution Tandem Mass Spectrometry

Folate and Colorectal Cancer in Rodents: A Model of DNA Repair Deficiency

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