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Functional Intersection of ATM and DNA-Dependent Protein Kinase Catalytic Subunit in Coding End Joining during V(D)J Recombination.
- Source :
-
Molecular & Cellular Biology . Sep2013, Vol. 33 Issue 18, p3568-3579. 11p. - Publication Year :
- 2013
-
Abstract
- V(D)J recombination is initiated by the RAG endonuclease, which introduces DNA double-strand breaks (DSBs) at the border between two recombining gene segments, generating two hairpin-sealed coding ends and two blunt signal ends. ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are serine-threonine kinases that orchestrate the cellular responses to DNA DSBs. During V(D)J recombination, ATM and DNA-PKcs have unique functions in the repair of coding DNA ends. ATM deficiency leads to instability of postcleavage complexes and the loss of coding ends from these complexes. DNA-PKcs deficiency leads to a nearly complete block in coding join formation, as DNA-PKcs is required to activate Artemis, the endonuclease that opens hairpin-sealed coding ends. In contrast to loss of DNA-PKcs protein, here we show that inhibition of DNA-PKcs kinase activity has no effect on coding join formation when ATM is present and its kinase activity is intact. The ability of ATM to compensate for DNA-PKcs kinase activity depends on the integrity of three threonines in DNA-PKcs that are phosphorylation targets of ATM, suggesting that ATM can modulate DNA-PKcs activity through direct phosphorylation of DNA-PKcs. Mutation of these threonine residues to alanine (DNA-PKcs3A) renders DNA-PKcs dependent on its intrinsic kinase activity during coding end joining, at a step downstream of opening hairpinsealed coding ends. Thus, DNA-PKcs has critical functions in coding end joining beyond promoting Artemis endonuclease activity, and these functions can be regulated redundantly by the kinase activity of either ATM or DNA-PKcs. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ENDONUCLEASES
*NUCLEASES
*PROTEIN kinases
*THREONINE
*MOLECULAR biology
*CYTOLOGY
Subjects
Details
- Language :
- English
- ISSN :
- 02707306
- Volume :
- 33
- Issue :
- 18
- Database :
- Academic Search Index
- Journal :
- Molecular & Cellular Biology
- Publication Type :
- Academic Journal
- Accession number :
- 90229810
- Full Text :
- https://doi.org/10.1128/MCB.00308-13