A family showing no evidence of linkage between the ataxia telangiectasia gene and chromosome 11q22-23.

Hernandez, Diana; McConville, Carmel; Stacey, Michael W.; Woods, C. G.; Brown, MA; Shutt, P.; Rysiecki, G; Taylor, Alexander M.

doi:10.1136/jmg.30.2.135

Cited by 66 publications

(31 citation statements)

References 17 publications

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“…Presently, the literature describes 18 cases of ATLD and one case of NBSLD that were all linked to mutations in the MRE11 gene and one NBSLD patient with two RAD50 mutations (Hernandez et al 1993;Stewart et al 1999;Pitts et al 2001;Delia et al 2004;Fernet et al 2005;Uchisaka et al 2009;Matsumoto et al 2011;Palmeri et al 2013). The availability of atomic structures of eukaryotic Mre11 and Nbs1 and prokaryotic Rad50 and the high degree of conservation of MRN allow us to map the underlying mutations onto a structural model of the MRN complex (Fig.…”

Section: Mutations In Mre11-rad50-nbs1 In Human Diseasementioning

confidence: 99%

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Schiller

Seifert

Linke-Winnebeck

et al. 2014

Cold Spring Harbor Perspectives in Biology

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DNA double-strand breaks are repaired by two major pathways, homologous recombination or nonhomologous end joining. The commitment to one or the other pathway proceeds via different steps of resection of the DNA ends, which is controlled and executed by a set of DNA double-strand break sensors, endo-and exonucleases, helicases, and DNA damage response factors. The molecular choreography of the underlying protein machinery is beginning to emerge. In this review, we discuss the early steps of genetic recombination and double-strand break sensing with an emphasis on structural and molecular studies.

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Section: Mutations In Mre11-rad50-nbs1 In Human Diseasementioning

confidence: 99%

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Schiller

Seifert

Linke-Winnebeck

et al. 2014

Cold Spring Harbor Perspectives in Biology

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“…Also, in CS there is degeneration of both granule and Purkinje neurons in the cerebellum [11]. Finally, regarding ATLD, while the clinical description of the original patients [20][21][22] was similar to a slowly progressing form of AT, some affected members of the most recently described family displayed microcephaly, similar to NBS patients [23]. Despite these caveats, Table 1 reflects the major neurologic features of the different diseases, and serves as a useful framework for considering the mechanisms discussed below.…”

Section: Caveatsmentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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“…A protein-truncating 5-bp NBS1 deletion, 657del5, has been found in most NBS families (more than 80%) with Slavic origins, demonstrating the presence of a common founder effect. Hernandez et al (1993) reported two cousins, a 25-year-old woman and a 20-year-old man, in a consanguineous family, who had many clinical features of AT, especially progressive cerebellar degeneration (Table 1). Cells from both patients showed radiosensitivity and chromosome instability, such as translocations including t(7;14)(p15;q32) and t(7;14)(q35;q11) seen in AT patients.…”

Section: Introductionmentioning

confidence: 99%

Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability

et al. 2002

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DNA double-strand breaks represent the most potentially serious damage to a genome and hence, at least two pathways of DNA repair have evolved; namely, homologous recombination repair and non-homologous end joining. Defects in both rejoining processes result in genomic instability including chromosome rearrangements, LOH and gene mutations, which may lead to development of malignancies. Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation that induces double-strand breaks, and high frequency of malignancies. NBS1, the product of the gene underlying the disease, forms a multimeric complex with hMRE11/ hRAD50 nuclease and recruits them to the vicinity of sites of DNA damage by direct binding to phosphorylated histone H2AX. The combination of the highlyconserved NBS1 forkhead associated domain and BRCA1 C-terminus domain has a crucial role for recognition of damaged sites. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. This process collaborates with cell-cycle checkpoints at S and G2 phase to facilitate DNA repair. NBS1 is also associated with telomere maintenance and DNA replication. Based on recent knowledge regarding NBS1, we propose here a two-step binding mechanism for damage recognition by repair proteins, and describe the molecular links to factors for genome stability.

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A family showing no evidence of linkage between the ataxia telangiectasia gene and chromosome 11q22-23.

Cited by 66 publications

References 17 publications

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Structural Studies of DNA End Detection and Resection in Homologous Recombination

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability

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