TDP1 promotes assembly of non-homologous end joining protein complexes on DNA |
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| Institution: | 1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA;2. Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Rockford Health Sciences Campus, 1601 Parkview Avenue, Rockford, IL 61107, USA;3. Department of Genetics, St. Jude Children''s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA;4. University of Manitoba, Department of Pharmacology and Therapeutics, Manitoba Institute of Cell Biology, 675 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0V9;1. Wellcome Trust Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, UK;2. Genome Damage Stability Centre, University of Sussex, Falmer Road, Brighton, BN1 9RQ, UK;3. Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama 35294;4. University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294;5. Department of Molecular Pharmacology, St. Jude Children''s Research Hospital, Memphis, Tennessee 38105;6. Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294;1. Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany;2. Computational Biology Group, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany |
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| Abstract: | The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. In tumor cells, the ability to repair DSBs predicts response to radiation and many cytotoxic anti-cancer drugs. DSB repair pathways include homologous recombination and non-homologous end joining (NHEJ). NHEJ is a template-independent mechanism, yet many NHEJ repair products carry limited genetic changes, which suggests that NHEJ includes mechanisms to minimize error. Proteins required for mammalian NHEJ include Ku70/80, the DNA-dependent protein kinase (DNA-PKcs), XLF/Cernunnos and the XRCC4:DNA ligase IV complex. NHEJ also utilizes accessory proteins that include DNA polymerases, nucleases, and other end-processing factors. In yeast, mutations of tyrosyl-DNA phosphodiesterase (TDP1) reduced NHEJ fidelity. TDP1 plays an important role in repair of topoisomerase-mediated DNA damage and 3′-blocking DNA lesions, and mutation of the human TDP1 gene results in an inherited human neuropathy termed SCAN1. We found that human TDP1 stimulated DNA binding by XLF and physically interacted with XLF to form TDP1:XLF:DNA complexes. TDP1:XLF interactions preferentially stimulated TDP1 activity on dsDNA as compared to ssDNA. TDP1 also promoted DNA binding by Ku70/80 and stimulated DNA-PK activity. Because Ku70/80 and XLF are the first factors recruited to the DSB at the onset of NHEJ, our data suggest a role for TDP1 during the early stages of mammalian NHEJ. |
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| Keywords: | Non-homologous end joining (NHEJ) TDP1 Ku70/80 XLF DNA-dependent protein kinase (DNA-PK) |
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