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

• Published in: Nature (London) 2000-06, Vol.405 (6788), p.807-810
• Main Authors: Wilson, Samuel H, Sobol, Robert W, Prasad, Rajendra, Evenski, Andrea, Baker, Audrey, Yang, Xiao-Ping, Horton, Julie K
• Format: Article
• Language: English
• Subjects: 5'-deoxyribose phosphate lyase; Biological and medical sciences; Cell Line; Cell Line, Transformed; Cellular biology; Chromosome aberrations; Cytotoxicity; Deoxyribonucleic acid; Deoxyribose - metabolism; DNA; DNA - biosynthesis; DNA - drug effects; DNA - metabolism; DNA ^b-polymerase; DNA Damage; DNA Methylation; DNA Polymerase beta - metabolism; DNA Repair; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Hypersensitivity; Lesions; letter; Lyases - metabolism; Methyl Methanesulfonate - toxicity; Molecular and cellular biology; Molecular genetics; multidisciplinary; Mutagenesis. Repair; Mutagens - toxicity; Proteins; Science; Science (multidisciplinary); Toxicity; Transfection
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35015598

Small DNA lesions such as oxidized or alkylated bases are repaired by the base excision repair (BER) pathway. BER includes removal of the damaged base by a lesion-specific DNA glycosylase, strand scission by apurinic/apyrimidinic endonuclease, DNA resynthesis and ligation. BER may be further subdivided into DNA β-polymerase (β-pol)-dependent single-nucleotide repair and β-pol-dependent or -independent long patch repair subpathways. 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). Fibroblasts from β-pol null mice are hypersensitive to monofunctional DNA-methylating agents, resulting in increases in chromosomal damage, apoptosis and necrotic cell death. 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.