Open AccessInhibition of Homologous Recombination by DNA-Dependent Protein Kinase Requires Kinase Activity, Is Titratable, and Is Modulated by Autophosphorylation
Author(s) -
Jessica A. Neal,
Van Duc Dang,
Pauline Douglas,
Marc S. Wold,
Susan P. LeesMiller,
Katheryn Meek
Publication year - 2011
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01298-10
Subject(s) - autophosphorylation , biology , dna repair , homologous recombination , non homologous end joining , dna pkcs , dna , protein kinase a , microbiology and biotechnology , dna repair protein xrcc4 , dna damage , phosphorylation , biochemistry , dna mismatch repair
How a cell chooses between nonhomologous end joining (NHEJ) and homologous recombination (HR) to repair a double-strand break (DSB) is a central and largely unanswered question. Although there is evidence of competition between HR and NHEJ, because of the DNA-dependent protein kinase (DNA-PK)'s cellular abundance, it seems that there must be more to the repair pathway choice than direct competition. Both a mutational approach and chemical inhibition were utilized to address how DNA-PK affects HR. We find that DNA-PK's ability to repress HR is both titratable and entirely dependent on its enzymatic activity. Still, although requisite, robust enzymatic activity is not sufficient to inhibit HR. Emerging data (including the data presented here) document the functional complexities of DNA-PK's extensive phosphorylations that likely occur on more than 40 sites. Even more, we show here that certain phosphorylations of the DNA-PK large catalytic subunit (DNA-PKcs) clearly promote HR while inhibiting NHEJ, and we conclude that the phosphorylation status of DNA-PK impacts how a cell chooses to repair a DSB.