An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome

O’Driscoll, Mark; Gennery, Andrew R.; Seidel, Jörg; Concannon, Patrick; Jeggo, Penny A.

doi:10.1016/j.dnarep.2004.03.025

Cited by 174 publications

(130 citation statements)

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“…Disease-causing mutations have been identified in Artemis, Lig4 and Cernunnos-XLF (Moshous et al, 2001;O'Driscoll et al, 2004;Revy et al, 2006). Radiosensitive severe combined immunodeficiency (RS-SCID) is associated with mutations in Artemis.…”

Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 99%

“…Hypomorphic mutations of LIG4 account for LIG4 syndrome, characterized by microcephaly, immunodeficiency, radiosensitivity and developmental delay (O'Driscoll et al, 2001(O'Driscoll et al, , 2004. LIG4 syndrome was first identified in a radiosensitive leukemia patient with a missense mutation (R278H), which was subsequently shown to decrease LIG4 adenylation and ligation activity by about 10% (Riballo et al, 1999(Riballo et al, , 2001O'Driscoll et al, 2004).…”

Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 99%

“…LIG4 syndrome was first identified in a radiosensitive leukemia patient with a missense mutation (R278H), which was subsequently shown to decrease LIG4 adenylation and ligation activity by about 10% (Riballo et al, 1999(Riballo et al, , 2001O'Driscoll et al, 2004). Additional LIG4 syndrome individuals have since been identified and display varying penetrance of the phenotype, due to differing hypomorphic mutations.…”

Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 99%

“…Defects in ATM and rad3-related (ATR) protein are also involved in aspects of the DNA damage response, and hypomorphic mutations can lead to Seckel syndrome (O'Driscoll et al, 2004;Stiff et al, 2005). While there is cross talk between ATM and ATR (Jazayeri et al, 2006;Matsuoka et al, 2007;Yoo et al, 2007), they have separable biochemical roles and complete ATR loss of function, like any of the MRN components, is incompatible with viability (Brown and Baltimore, 2000).…”

Section: Defective Dna Dsb Responses and A-t-related Syndromesmentioning

confidence: 99%

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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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Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 99%

Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 99%

Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 99%

Section: Defective Dna Dsb Responses and A-t-related Syndromesmentioning

confidence: 99%

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DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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“…This renders the appearance of a pronounced nose and underlies the dysmorphic facial features also observed in LIG4 Syndrome and XLF-deficient patients, a feature also observed in Seckel Syndrome [98]. The growth delay observed in NHEJ-deficient patients could be the result of a similar impact of unrepaired DSBs on cell loss (via apoptosis or merely a failure to replicate) in other stem cell compartments.…”

Section: How Does Nhej Deficiency Confer Microcephaly and Growth Delaymentioning

confidence: 90%

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

2014

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Double strand break repair V(D)J recombination (Severe) combined immunodeficiency -(S)CID Human syndromes a b s t r a c t DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency -(S)CID -due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology.

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DNA Damage Response: From Tumourigenesis to Therapy

Bain

Mastrocola

Tibbetts

et al. 2014

Encyclopedia of Life Sciences

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The deoxyribonucleic acid (DNA) damage response (DDR) pathway is a surveillance network, whereby lesions are eliminated from DNA to ensure genomic integrity. The DDR detects aberrant DNA and chromosomal structures and elicits a multifaceted response network to coordinate multiple cellular processes, including regulation of the cell cycle, DNA repair, replication and, under certain circumstances, the triggering of programmed cell death. However, when the DDR is dysregulated, genomic integrity is not ensured, which may lead to tumourigenesis. Paradoxically, although genomic instability is a hallmark of many cancers, many conventional cancer treatments elicit the generation of additional DNA damage to exploit inherent DDR faults present in tumour cells. In addition, new‐targeted DDR inhibitors are currently being developed to enhance therapeutic indexes, including those that are synthetically lethal in particular tumour cell types, providing exciting new therapeutic avenues for cancer treatment. The challenge is how to identify the patients most receptive to these treatments. Key Concepts: Genome stability is critical to prevent tumourigenesis. Cell cycle checkpoints and DNA repair exist to prevent faulty genetic information from passing onto daughter cells. Many cancer types exhibit defective DNA repair pathways. DNA repair is an ideal therapeutic target for cancer. Cancers exhibit multiple chromosomal alterations. Inherited mutations in DNA repair genes can cause chromosomal instability disorders.

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An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome

Cited by 174 publications

References 50 publications

DNA double-strand break repair and development

DNA double-strand break repair and development

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

DNA Damage Response: From Tumourigenesis to Therapy

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