Requirement for Ku80 in growth and immunoglobulin V(D)J recombination

Nussenzweig, André; Chen, C; Soares, Vera da Costa; Sanchez, Mercedes; Sokol, Karen; Nussenzweig, Michel C.; Li, G C

doi:10.1038/382551a0

Cited by 611 publications

(539 citation statements)

References 28 publications

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“…These results suggest that the transport of Ku70 and Ku80 is regulated independently. In recent studies using knock-out mice, inactivation of Ku70 resulted in a phenotype distinct from that of Ku80 (Nussenzweig et al, 1996;Gu et al, 1997;Ouyang et al, 1997;Li et al, 1998). Fibroblasts derived from Ku70-knockout mice exhibit signi®cantly higher frequencies of sister chromatid exchanges and spontaneous neoplastic transformation relative to wild-type controls (Li et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…A large body of evidence obtained from in vitro studies suggests that DNA-PK is involved in the repair of DNA doublestrand breaks (DSB) and V(D)J recombination Jeggo et al, 1995). Both Ku70-and Ku80-knockout mice which showed not only de®ciencies in DSB repair and V(D)J recombination, but also growth retardation, were generated recently (Nussenzweig et al, 1996;Gu et al, 1997;Ouyang et al, 1997). Null knockout mice for the catalytic subunit (DNA-PKcs) of DNA-PK also showed de®ciencies in DSB repair and V(D)J recombination, but not growth retardation (Gao et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Ku80 can translocate to the nucleus independent of the translocation of Ku70 using its own nuclear localization signal

Koike¹,

Ikuta

Miyasaka³

et al. 1999

Oncogene

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Ku antigen is a complex of Ku70 and Ku80 subunits and plays an important role in not only DNA double-strand breaks (DSB) repair and V(D)J recombination, but also in growth regulation. Ku is generally believed to always form and function as heterodimers on the basis of in vitro observations. Here we demonstrate that the localization of Ku80 does not completely coincide with that of Ku70. Ku70 and Ku80 were colocalized in the nucleus in the interphase but not in the late telophase/early G1 phase of the cell cycle. Since the in vivo function of Ku might be partially regulated by the control of its transport, we attempted to investigate the molecular mechanisms underlying the nuclear translocation of Ku. The nuclear translocation of Ku80 started during the late telophase/ early G1 phase after the nuclear envelope was formed and this was preceded by the nuclear translocation of Ku70. Furthermore, we found that the Ku80 protein was transported to the nucleus without heterodimerization with Ku70. To understand in detail the mechanism of transport of Ku80, we attempted to identify the nuclear localization signal (NLS) of Ku80 and de®ned to a region spanning nine amino acid residues (positions 561 ± 569). The Ku80 NLS was demonstrated to be mediated to the nuclear rim by two components of PTAC58 and PTAC97. All these ®ndings support the idea that Ku80 can translocate to the nucleus using its own NLS independent of the translocation of Ku70.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ku80 can translocate to the nucleus independent of the translocation of Ku70 using its own nuclear localization signal

Koike¹,

Ikuta

Miyasaka³

et al. 1999

Oncogene

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show abstract

“…Ku70 À/À and Ku80 À/À mice, while viable, likewise showed increased apoptosis in post-mitotic neural cells, though to a lesser extent than seen in Xrcc4 À/À and Lig4 À/À embryos (Gu et al, 2000). Ku70/80 deficiency also imparts radiation sensitivity, proportional dwarfism, impaired V(D)J recombination, abrogation of DSB repair, predisposition to thymic lymphomas and impaired B-cell development (Nussenzweig et al, 1996;Gu et al, 1997;Ouyang et al, 1997). The DNA-PK phenotype is less severe than that of the Ku-deficient mice, as they exhibit no growth defect or radiation sensitivity despite immunodeficiency (Taccioli et al, 1998;Gao et al, 1998a).…”

Section: Animal Models Of Nhej and Hr Deficienciesmentioning

confidence: 94%

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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“…As Ku70/Ku80 and DNA‐PKcs modulate RAG‐mediated cleavage6 by assisting the selection of proper RSS combination, this implies that the DNA–PK complex might be involved in the recombination process upstream of RAG cleavage. Indeed, in mice Ku70 and/or Ku80 are absolutely essential for V(D)J recombination and their deletion leads to severe combined immunodeficiency (SCID) 7, 8. As of yet, Ku70/80 mutations have not been identified in patients.…”

Section: Mechanisms Of Recombination In Lymphoid Cellsmentioning

confidence: 99%

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Procházková

Loizou

2015

Immunology

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SummaryIn recent years, several novel congenital human disorders have been described with defects in lymphoid B‐cell and T‐cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double‐strand break repair, as well as compromised DNA damage‐induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways.

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Requirement for Ku80 in growth and immunoglobulin V(D)J recombination

Cited by 611 publications

References 28 publications

Ku80 can translocate to the nucleus independent of the translocation of Ku70 using its own nuclear localization signal

Ku80 can translocate to the nucleus independent of the translocation of Ku70 using its own nuclear localization signal

DNA double-strand break repair and development

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

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