Inhibition of Homologous Recombination by DNA-Dependent Protein Kinase Requires Kinase Activity, Is Titratable, and Is Modulated by Autophosphorylation

Jessica A Neal; Van Dang; Pauline Douglas; Marc S Wold; Susan P Lees-Miller; Katheryn Meek

doi:10.1128/MCB.01298-10

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Inhibition of Homologous Recombination by DNA-Dependent Protein Kinase Requires Kinase Activity, Is Titratable, and Is Modulated by Autophosphorylation

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Inhibition of Homologous Recombination by DNA-Dependent Protein Kinase Requires Kinase Activity, Is Titratable, and Is Modulated by Autophosphorylation

Jessica A Neal, Van Dang, Pauline Douglas, Marc S Wold, Susan P Lees-Miller and Katheryn Meek

Molecular and cellular biology, Vol.31(8), pp.1719-1733

04/2011

DOI: 10.1128/MCB.01298-10

PMCID: PMC3126343

PMID: 21300785

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https://www.ncbi.nlm.nih.gov/pmc/articles/3126343View

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Abstract

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.

Details

Title: Subtitle: Inhibition of Homologous Recombination by DNA-Dependent Protein Kinase Requires Kinase Activity, Is Titratable, and Is Modulated by Autophosphorylation
Creators: Jessica A Neal - College of Veterinary Medicine, Department of Microbiology & Molecular Genetics, and Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
Van Dang - College of Veterinary Medicine, Department of Microbiology & Molecular Genetics, and Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
Pauline Douglas - Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada T2N4N1
Marc S Wold - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
Susan P Lees-Miller - Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada T2N4N1
Katheryn Meek - College of Veterinary Medicine, Department of Microbiology & Molecular Genetics, and Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.31(8), pp.1719-1733
DOI: 10.1128/MCB.01298-10
PMID: 21300785
PMCID: PMC3126343
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Publisher: American Society for Microbiology; 1752 N St., N.W., Washington, DC
Language: English
Date published: 04/2011
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984024417102771

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