The lyase activity of the DNA repair protein β-polymerase protects from DNA-damage-induced cytotoxicity

Robert W. Sobol, Rajendra Prasad, Andrea Evenski, Audrey Baker, Xiao-Ping Yang, Julie K. Horton and Samuel H. Wilson ()
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Robert W. Sobol: Laboratory of Structural Biology, National Institute of Environmental Health Sciences
Rajendra Prasad: Laboratory of Structural Biology, National Institute of Environmental Health Sciences
Andrea Evenski: Laboratory of Structural Biology, National Institute of Environmental Health Sciences
Audrey Baker: Laboratory of Structural Biology, National Institute of Environmental Health Sciences
Xiao-Ping Yang: Laboratory of Structural Biology, National Institute of Environmental Health Sciences
Julie K. Horton: Laboratory of Structural Biology, National Institute of Environmental Health Sciences
Samuel H. Wilson: Laboratory of Structural Biology, National Institute of Environmental Health Sciences

Nature, 2000, vol. 405, issue 6788, 807-810

Abstract: Abstract Small DNA lesions such as oxidized or alkylated bases are repaired by the base excision repair (BER) pathway1. BER includes removal of the damaged base by a lesion-specific DNA glycosylase, strand scission by apurinic/apyrimidinic endonuclease, DNA resynthesis and ligation2. BER may be further subdivided into DNA β-polymerase (β-pol)-dependent single-nucleotide repair and β-pol-dependent or -independent long patch repair subpathways3,4,5,6. Two important enzymatic steps in mammalian single-nucleotide BER are contributed by β-pol: DNA resynthesis of the repair patch and lyase removal of 5′-deoxyribose phosphate (dRP)2. Fibroblasts from β-pol null mice are hypersensitive to monofunctional DNA-methylating agents, resulting in increases in chromosomal damage, apoptosis and necrotic cell death3,7. Here we show that only the dRP lyase activity of β-pol is required to reverse methylating agent hypersensitivity in β-pol null cells. These results indicate that removal of the dRP group is a pivotal step in BER in vivo. Persistence of the dRP moiety in DNA results in the hypersensitivity phenotype of β-pol null cells and may signal downstream events such as apoptosis and necrotic cell death.

Date: 2000
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DOI: 10.1038/35015598

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