From xeroderma pigmentosum to the biological clock contributions of Dirk Bootsma to human genetics

Hoeijmakers, Jan H.J.

doi:10.1016/s0921-8777(00)00079-3

Cited by 6 publications

(4 citation statements)

References 83 publications

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“…In addition, Ku80 mice with a defect in NHEJ exhibit an early onset of aging characteristics as among others a shortened life span, cancer, reduced weight, osteopenia, and alopecia. In Ercc1 and Xpf mutant mice, with a defect in NER and inter-strand cross-link repair, liver and kidney abnormalities reminiscent of accelerated aging are present in addition to reduced life span, body weight and progressive neuronal dysfunction [98]. In case of the Ercc1/Xpf mice later the corresponding human XFE syndrome was identified with many prominent features of premature aging, noted before in the mouse, strengthening the validity of mouse models for understanding the human syndromes (see also article by Gregg et al in this issue of DNA Repair).…”

Section: Other Mouse Models Showing Premature Agingmentioning

confidence: 99%

Premature aging and cancer in nucleotide excision repair-disorders

Diderich¹,

Alanazi²,

Hoeijmakers³

2011

DNA Repair

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During past decades the major impact of DNA damage on cancer as ‘disease of the genes’ has become abundantly apparent. In addition to cancer recent years have also uncovered a very strong association of DNA damage with many features of (premature) aging. The notion that DNA repair systems not only protect against cancer but equally against too fast aging has become evident from a systematic, integral analysis of a variety of mouse mutants carrying defects in e.g. transcription-coupled repair with or without an additional impairment of global genome nucleotide excision repair and the corresponding segmental premature aging syndromes in man. A striking correlation between the degree of the DNA repair deficiency and the acceleration of specific progeroid symptoms has been discovered for those repair systems that primarily protect from the cytotoxic and cytostatic effects of DNA damage. These observations are explained from the perspective of nucleotide excision repair mouse mutant and human syndromes. However, similar principles likely apply to other DNA repair pathways including interstrand crosslink repair and double strand break repair and genome maintenance systems in general, supporting the notion that DNA damage constitutes an important intermediate in the process of aging.

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Section: Other Mouse Models Showing Premature Agingmentioning

confidence: 99%

Premature aging and cancer in nucleotide excision repair-disorders

Diderich¹,

Alanazi²,

Hoeijmakers³

2011

DNA Repair

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“…Thus, risk of melanoma and non-melanoma skin cancers has been reported to be increased 2 to 10 thousand-fold, respectively [2] . XP cells are deficient in the nucleotide excision repair (NER) pathway, a complex process involved in the recognition and removal of DNA lesions induced by UV light (cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts) [3] . Seven different genes named XPA to XPG are involved in that process.…”

Section: Introductionmentioning

confidence: 99%

Targeted Gene Therapy of Xeroderma Pigmentosum Cells Using Meganuclease and TALEN™

Dupuy

Valton²,

Leduc³

et al. 2013

PLoS ONE

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Xeroderma pigmentosum group C (XP-C) is a rare human syndrome characterized by hypersensitivity to UV light and a dramatic predisposition to skin neoplasms. XP-C cells are deficient in the nucleotide excision repair (NER) pathway, a complex process involved in the recognition and removal of DNA lesions. Several XPC mutations have been described, including a founder mutation in North African patients involving the deletion of a TG dinucleotide (ΔTG) located in the middle of exon 9. This deletion leads to the expression of an inactive truncated XPC protein, normally involved in the first step of NER. New approaches used for gene correction are based on the ability of engineered nucleases such as Meganucleases, Zinc-Finger nucleases or TALE nucleases to accurately generate a double strand break at a specific locus and promote correction by homologous recombination through the insertion of an exogenous DNA repair matrix. Here, we describe the targeted correction of the ΔTG mutation in XP-C cells using engineered meganuclease and TALEN™. The methylated status of the XPC locus, known to inhibit both of these nuclease activities, led us to adapt our experimental design to optimize their in vivo efficacies. We show that demethylating treatment as well as the use of TALEN™ insensitive to CpG methylation enable successful correction of the ΔTG mutation. Such genetic correction leads to re-expression of the full-length XPC protein and to the recovery of NER capacity, attested by UV-C resistance of the corrected cells. Overall, we demonstrate that nuclease-based targeted approaches offer reliable and efficient strategies for gene correction.

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“…ERCC1 is involved in both recognition of the damage and excision of the damaged part of DNA 13 . The analysis of allelic polymorphism of ERCC1 in HNSCC samples of this study revealed that the frequency of ERCC1 G19007A was 0.79 for allele A.…”

Section: Discussionmentioning

confidence: 60%