scholarly journals Genetic Analysis of the DNA-dependent Protein Kinase Reveals an Inhibitory Role of Ku in Late S–G2Phase DNA Double-strand Break Repair

2001 ◽  
Vol 276 (48) ◽  
pp. 44413-44418 ◽  
Author(s):  
Toru Fukushima ◽  
Minoru Takata ◽  
Ciaran Morrison ◽  
Ryoko Araki ◽  
Akira Fujimori ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Genetic Analysis ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dependent Protein Kinase ◽  
Inhibitory Role ◽  
Dna Double Strand Break ◽  
Dependent Protein

DNA-dependent protein kinase defects are linked to deficiencies in DNA repair and V(D)J recombination

1996 ◽  
Vol 351 (1336) ◽  
pp. 173-179 ◽  
Keyword(s):  
Protein Kinase ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dependent Protein Kinase ◽  
Dna Double Strand Break ◽  
Genes Encoding ◽  
Dependent Protein ◽  
Break Repair ◽  
Functional Dna

DNA-dependent protein kinase is a nuclear serine/threonine kinase whose catalytic properties are expressed only when the enzyme is bound to DNA ends or other discontinuities in the DNA. DNA-PK comprises two components: one mediates binding to DNA and corresponds to the heterodimeric human autoimmune antigen Ku; the other, DNA-PK catalytic subunit (DNA-PKCS), is a polypeptide of approximately 450 kDa. DNA-PK deficiencies are associated with certain mutant rodent cell lines that display defects in DNA double strand break repair and V(D)J recombination. Specifically, hamster xrs- 6 cells lack Ku function, whereas murine scid and hamster V3 cells lack functional DNA-PKCS. Furthermore, the phenotypes of xrs-6 and V3 cells can be corrected by the expression of the genes encoding the 80 kDa component of Ku or DNA-PKCS, respectively. These results imply that DNA-PK is an important component of the DNA double strand break repair/recombination apparatus. Possible roles for DNA-PK in these processes are discussed.

scholarly journals SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair

Aging ◽  
2009 ◽  
Vol 1 (1) ◽  
pp. 109-121 ◽  
Author(s):  
Ronald A. McCord ◽  
Eriko Michishita ◽  
Tao Hong ◽  
Elisabeth Berber ◽  
Lisa D. Boxer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dependent Protein Kinase ◽  
Dna Double Strand Break ◽  
Dependent Protein ◽  
Break Repair

Variation in DNA Repair Genes XRCC3, XRCC4, and XRCC5 and Risk of Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3416-3416
Author(s):  
Patrick Hayden ◽  
Prerna Tewari ◽  
Anthony Staines ◽  
Derek Morris ◽  
Dominique Crowley ◽  
...  
Keyword(s):  
Dna Repair ◽  
Protein Kinase ◽  
Strand Break ◽  
Double Strand Break ◽  
Drop Out ◽  
Early Event ◽  
Dna Double Strand Breaks ◽  
Dependent Protein Kinase ◽  
Dna Double Strand Break ◽  
Dependent Protein

Abstract Aberrant class switch recombination (CSR), the physiological process that regulates maturation of the antibody response, is believed to be an early event in the pathogenesis of myeloma. The genetic basis of CSR, from initiation of the DNA double-strand break through to detection and repair, has been elucidated. We hypothesised that germline polymorphisms in the genes implicated in DNA double strand break repair may contribute to susceptibility to myeloma. We therefore assessed 32 SNPs in 3 genes central to the DNA repair pathway in patients with myeloma and controls from the EpiLymph Study, a European study of the epidemiology of lymphoid neoplasms, and from an Irish hospital registry (306 cases, 263 controls). The genes examined were XRCC3, XRCC4, and XRCC5. XRCC3 is a member of the RecA/Rad51-related protein family that participates in homologous recombination. The XRCC4 protein forms a complex with DNA ligase IV and DNA-dependent protein kinase in the repair of DNA double-strand breaks by non-homologous end joining. XRCC5 encodes the 80-kilodalton subunit of the Ku heterodimer protein, the DNA-binding component of the DNA-dependent protein kinase. SNPs from the chosen genes were identified from HapMap CEU Phase I and II genotype data (Public Release #20; 2006-01-24). Haplotype-tagging SNPs (htSNPs) were chosen based on Tagger analysis (as implemented in Haploview Version 3.2). A SNP in GSTP1 was also genotyped to allow for comparison with allele frequencies previously generated from a myeloma cohort. Genotyping was performed using TaqMan®-based assays on the 7900 ABI HT platform. The drop-out rate was consistently less than 3% in all assays. For quality control (QC) purposes, duplicates of 10% of the samples were interspersed throughout the plates. The concordance rates for QC samples were greater than 98%. GSTP1 SNP results were comparable to previously published findings. For the htSNP rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4% vs.80.8%) (p=0.0105), as was the AA genotype (74% vs. 65%) (p=0.026). Haplotype analysis was performed using Cocaphase for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A - T haplotype from rs963248-rs2891980 (80.9% vs. 74.5%; p=0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only 1 control (p=0.015). Interestingly, this SNP is located in the 3′ UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.

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