Role and regulation of human XRCC4‐like factor/cernunnos

Dahm, Kirsten

doi:10.1002/jcb.21726

Cited by 13 publications

(14 citation statements)

References 25 publications

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“…14 Phosphorylation of DNA-PKcs, either trans-autophosphorylation or by ATM, promotes its dissociation from DNA ends, 20 and enhances access by the Ligase IV/XRCC4/XLF protein complex, which completes the ligation reaction. 21 Defects in classic NHEJ proteins channel DSBs toward alternative NHEJ (Alt-NHEJ), a robust but less accurate pathway that is regulated by PARP1 13 binding to the free DNA ends instead of the Ku complex. This pathway requires single-strand end-resection by the MRE11/RAD50/NBS1 (MRN) complex, 22 and the CtIP tumor-suppressor.…”

Section: Mechanisms Of Dna Repairmentioning

confidence: 99%

Synthetic lethality: exploiting the addiction of cancer to DNA repair

Shaheen

Allen

Nickoloff

et al. 2011

Blood

170

193

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Because cancer at its origin must acquire permanent genomic mutations, it is by definition a disease of DNA repair. Yet for cancer cells to replicate their DNA and divide, which is the fundamental phenotype of cancer, multiple DNA repair pathways are required. This produces a paradox for the cancer cell, where its origin is at the same time its weakness. To overcome this difficulty, a cancer cell often becomes addicted to DNA repair pathways other than the one that led to its initial mutability. The best example of this is in breast or ovarian cancers with mutated BRCA1 or 2, essential components of a repair pathway for repairing DNA double-strand breaks. Because replicating DNA requires repair of DNA doublestrand breaks, these cancers have become reliant on another DNA repair component, PARP1, for replication fork progression. The inhibition of PARP1 in these cells results in catastrophic doublestrand breaks during replication, and ultimately cell death. The exploitation of the addiction of cancer cells to a DNA repair pathway is based on synthetic lethality and has wide applicability to the treatment of many types of malignancies, including those of hematologic origin. There is a large number of novel compounds in clinical trials that use this mechanism for their antineoplastic activity, making synthetic lethality one of the most important new concepts in recent drug development.

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Section: Mechanisms Of Dna Repairmentioning

confidence: 99%

Synthetic lethality: exploiting the addiction of cancer to DNA repair

Shaheen

Allen

Nickoloff

et al. 2011

Blood

170

193

View full text Add to dashboard Cite

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“…In contrast, the 3' overhangs are clipped with a preference for leaving a 4-or 5-nuleotide single-stranded overhang (10). After autophosphorylation, DNA-PKcs recruits XRCC4/ligase Ⅳ complex to process the DNA ends and to initiate re-ligation to form a single DNA molecule (5,11,12). Thus, targeted inhibition of DSB repair proteins is an attractive approach in the development of potent radiation therapy strategies (13,14).…”

Section: Introductionmentioning

confidence: 99%

Suppression of DNA-PKcs and Ku80 individually and in combination: Different effects of radiobiology in HeLa cells

Huang

2011

Int J Oncol

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Abstract. DNA-dependent protein kinase (DNA-PK), including Ku80, Ku70 and DNA-PK catalytic subunit (DNA-PKcs), is the key protein in non-homologous end-joining (NHEJ) after DNA double-strand breaks (DSBs) appear. In this study, small hairpin interfering RNAs (siRNAs) targeting Ku80 and DNAPKcs were used both individually and in combination, to explore the effects of these DSB proteins on HeLa cell functional changes after X-ray irradiation. HeLa cells co-transfected with Ku80-siRNA and DNA-PKcs-siRNA were more radiosensitive than the ones transfected individually. HeLa in the absence of Ku80 and pretreated with LY294002, a chemically specific PI 3-kinase inhibitor, resulted in cells that were even more sensitive to X-rays than HeLa/Ku80-siRNA transfected with DNAPKcs-siRNA. The cells inhibited by Ku80 either individually or in combination with DNA-PKcs showed cell accumulation in the G2/M phase 48 h post-irradiation, similarly to control cells. However, cells transfected with DNA-PKcs-siRNA or pretreated with LY294002 had a prolonged G2/M delay, suggesting the accumulation of significant un-repaired DNA damage following inhibition of DSB repair proteins. In conclusion, these data indicate that the role of Ku80 in DSB repair could be compensated by other DSB repair proteins; co-inhibition would be a suitable strategy to enhance the radiosensitivity of cancer cells.

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“…19,20 So far, the most important action of XLF seems to be the stimulation of LIG4 activity, 21,22 probably by stabilizing the XRCC4-LIG4 complex on DNA and promotion of DNA strand alignment. 23 However, recently, Lescale et al have shown that the RAG postcleavage complex (RAG-PCC) and XLF have overlapping functions and have suggested that both the RAG-PCC and XLF ensure stabilization of DNA ends after DNA cleavage by RAG. 24 To further understand the function of XLF during V(D)J recombination and NHEJ, the characteristics of the immunoglobulin heavy chain (IgH), Igk (IgK), Igl (IgL), TR b (TRB), and TR d (TRD) gene rearrangements were studied in 6 XLF-deficient patients, using nextgeneration sequencing.…”

Section: Introductionmentioning

confidence: 99%

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

IJspeert

Rozmus

Schwarz

et al. 2016

Blood

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Key Points• XLF belongs to the NHEJ ligation complex and has a dual role in DNA doublestrand break repair and V(D)J recombination.• XLF is involved in Nnucleotide addition, and thereby contributes to junctional diversity of the antigen receptors.Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex. However, the effect on the immune system is variable (mild to severe immunodeficiency) and less prominent than that seen in deficiencies of NHEJ factors ARTEMIS and DNA-dependent protein kinase catalytic subunit, with defects in the hairpin opening step, which is crucial and unique for V(D)J recombination. Therefore, we aimed to study the role of XLF during V(D)J recombination. We obtained clinical data from 9 XLF-deficient patients and performed immune phenotyping and antigen receptor repertoire analysis of immunoglobulin (Ig) and T-cell receptor (TR) rearrangements, using next-generation sequencing in 6 patients. The results were compared with XRCC4 and LIG4 deficiency. Both Ig and TR rearrangements showed a significant decrease in the number of nontemplated (N) nucleotides inserted by terminal deoxynucleotidyl transferase, which resulted in a decrease of 2 to 3 amino acids in the CDR3. Such a reduction in the number of N-nucleotides has a great effect on the junctional diversity, and thereby on the total diversity of the Ig and TR repertoire. This shows that XLF has an important role during V(D)J recombination in creating diversity of the repertoire by stimulating N-nucleotide insertion. (Blood. 2016;128(5):650-659)

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Role and regulation of human XRCC4‐like factor/cernunnos

Cited by 13 publications

References 25 publications

Synthetic lethality: exploiting the addiction of cancer to DNA repair

Synthetic lethality: exploiting the addiction of cancer to DNA repair

Suppression of DNA-PKcs and Ku80 individually and in combination: Different effects of radiobiology in HeLa cells

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

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