scholarly journals DNA-Dependent Protein Kinase Catalytic Subunit: The Sensor for DNA Double-Strand Breaks Structurally and Functionally Related to Ataxia Telangiectasia Mutated

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1143
Author(s):  
Yoshihisa Matsumoto ◽  
Anie Day D. C. Asa ◽  
Chaity Modak ◽  
Mikio Shimada
Keyword(s):  
Protein Kinase ◽  
Ataxia Telangiectasia ◽  
Catalytic Subunit ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
End Joining ◽  
Dependent Protein Kinase ◽  
Strand Breaks ◽  
Dependent Protein

The DNA-dependent protein kinase (DNA-PK) is composed of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer. DNA-PK is thought to act as the “sensor” for DNA double-stranded breaks (DSB), which are considered the most deleterious type of DNA damage. In particular, DNA-PKcs and Ku are shown to be essential for DSB repair through nonhomologous end joining (NHEJ). The phenotypes of animals and human individuals with defective DNA-PKcs or Ku functions indicate their essential roles in these developments, especially in neuronal and immune systems. DNA-PKcs are structurally related to Ataxia–telangiectasia mutated (ATM), which is also implicated in the cellular responses to DSBs. DNA-PKcs and ATM constitute the phosphatidylinositol 3-kinase-like kinases (PIKKs) family with several other molecules. Here, we review the accumulated knowledge on the functions of DNA-PKcs, mainly based on the phenotypes of DNA-PKcs-deficient cells in animals and human individuals, and also discuss its relationship with ATM in the maintenance of genomic stability.

scholarly journals DNA-dependent Protein Kinase Activity Is Not Required for Immunoglobulin Class Switching

2002 ◽  
Vol 196 (11) ◽  
pp. 1483-1495 ◽  
Author(s):  
Gayle C. Bosma ◽  
Jiyoon Kim ◽  
Teresa Urich ◽  
Donna M. Fath ◽  
Maria G. Cotticelli ◽  
...  
Keyword(s):  
B Cells ◽  
Protein Kinase ◽  
Scid Mice ◽  
Nonhomologous End Joining ◽  
Protein Kinase Activity ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
End Joining ◽  
Dependent Protein Kinase ◽  
Dependent Protein

Class switch recombination (CSR), similar to V(D)J recombination, is thought to involve DNA double strand breaks and repair by the nonhomologous end–joining pathway. A key component of this pathway is DNA-dependent protein kinase (DNA-PK), consisting of a catalytic subunit (DNA-PKcs) and a DNA-binding heterodimer (Ku70/80). To test whether DNA-PKcs activity is essential for CSR, we examined whether IgM+ B cells from scid mice with site-directed H and L chain transgenes were able to undergo CSR. Although B cells from these mice were shown to lack DNA-PKcs activity, they were able to switch from IgM to IgG or IgA with close to the same efficiency as B cells from control transgenic and nontransgenic scid/+ mice, heterozygous for the scid mutation. We conclude that CSR, unlike V(D)J recombination, can readily occur in the absence of DNA-PKcs activity. We suggest nonhomologous end joining may not be the (primary or only) mechanism used to repair DNA breaks during CSR.

scholarly journals Artemis and Nonhomologous End Joining-Independent Influence of DNA-Dependent Protein Kinase Catalytic Subunit on Chromosome Stability

2008 ◽  
Vol 29 (2) ◽  
pp. 503-514 ◽  
Author(s):  
Travis H. Stracker ◽  
Bret R. Williams ◽  
Ludovic Deriano ◽  
Jan W. Theunissen ◽  
Carrie A. Adelman ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Cell Cycle Checkpoint ◽  
Catalytic Subunit ◽  
Nonhomologous End Joining ◽  
Chromosome Stability ◽  
End Joining ◽  
Dependent Protein Kinase ◽  
Dependent Protein

ABSTRACT Deficiency in both ATM and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is synthetically lethal in developing mouse embryos. Using mice that phenocopy diverse aspects of Atm deficiency, we have analyzed the genetic requirements for embryonic lethality in the absence of functional DNA-PKcs. Similar to the loss of ATM, hypomorphic mutations of Mre11 (Mre11 ATLD1 ) led to synthetic lethality when juxtaposed with DNA-PKcs deficiency (Prkdc scid ). In contrast, the more moderate DNA double-strand break response defects associated with the Nbs1 ΔB allele permitted viability of some Nbs1 Δ B/ Δ B Prkdc scid/scid embryos. Cell cultures from Nbs1 Δ B/ Δ B Prkdc scid/scid embryos displayed severe defects, including premature senescence, mitotic aberrations, sensitivity to ionizing radiation, altered checkpoint responses, and increased chromosome instability. The known functions of DNA-PKcs in the regulation of Artemis nuclease activity or nonhomologous end joining-mediated repair do not appear to underlie the severe genetic interaction. Our results reveal a role for DNA-PKcs in the maintenance of S/G2-phase chromosome stability and in the induction of cell cycle checkpoint responses.

scholarly journals DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP

2018 ◽  
Author(s):  
Rajashree A. Deshpande ◽  
Logan R. Myler ◽  
Michael M. Soniat ◽  
Nodar Makharashvili ◽  
Linda Lee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Homologous Recombination ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dependent Protein Kinase ◽  
Strand Breaks ◽  
Mrn Complex ◽  
Dependent Protein ◽  
Non Homologous End Joining ◽  
Dna Ends

AbstractThe repair of DNA double-strand breaks occurs through non-homologous end joining or homologous recombination in vertebrate cells - a choice that is thought to be decided by a competition between DNA-dependent protein kinase (DNA-PK) and the Mre11/Rad50/Nbs1 (MRN) complex but is not well understood. Using ensemble biochemistry and single-molecule approaches, here we show that the MRN complex is dependent on DNA-PK and phosphorylated CtIP to perform efficient processing and resection of DNA ends in physiological conditions, thus eliminating the competition model. Endonucleolytic removal of DNA-PK-bound DNA ends is also observed at double-strand break sites in human cells. The involvement of DNA-PK in MRN-mediated end processing promotes an efficient and sequential transition from non-homologous end joining to homologous recombination by facilitating DNA-PK removal.One Sentence SummaryDNA-dependent protein kinase, an enzyme critical for non-homologous repair of DNA double-strand breaks, also stimulates end processing for homologous recombination.

scholarly journals Somatic Hypermutation in the Absence of DNA-Dependent Protein Kinase Catalytic Subunit (DNA-Pkcs) or Recombination-Activating Gene (Rag)1 Activity

2000 ◽  
Vol 192 (10) ◽  
pp. 1509-1514 ◽  
Author(s):  
Mats Bemark ◽  
Julian E. Sale ◽  
Hye-Jung Kim ◽  
Claudia Berek ◽  
Ruth A. Cosgrove ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Catalytic Subunit ◽  
Antigen Receptors ◽  
End Joining ◽  
Dependent Protein Kinase ◽  
Recombination Activating Gene ◽  
Dependent Protein ◽  
Rag 1

Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-switch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs)/Ku complex and likely involves nonhomologous end joining (NHEJ). That somatic hypermutation might also be associated with end joining is suggested by its association with the creation of deletions, duplications, and sites accessible to terminal transferase. However, a requirement for NHEJ in the mutation process has not been demonstrated. Here we show that somatic mutation in mice deficient in NHEJ can be tested by introduction of rearranged immunoglobulin and T cell receptor transgenes: the transgene combination not only permits reconstitution of peripheral lymphoid compartments but also allows formation of germinal centers, despite the wholly monoclonal nature of the lymphocyte antigen receptors in these animals. Using this strategy, we confirm that somatic hypermutation like class-switching can occur in the absence of recombination-activating gene (RAG)1 but show that the two processes differ in that hypermutation can proceed essentially unaffected by deficiency in DNA-PKcs activity.

Sign in / Sign up

Export Citation Format

Share Document