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EMBO reports 9, 5, 459–464 (2008)
doi:10.1038/embor.2008.33
AOP Published online: 28 March 2008
Substrate-induced DNA strand misalignment during catalytic cycling by DNA polymerase 
EMBO Open
Katarzyna Bebenek1*, Miguel Garcia-Diaz1†*, Meredith C Foley2, Lars C Pedersen1, Tamar Schlick2 & Thomas A Kunkel1
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1 Laboratory of Structural Biology and Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
2 Department of Chemistry, Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, New York 10012, USA
To whom correspondence should be addressed
Thomas A Kunkel Tel: +1 919 541 2644; Fax: +1 919 541 7613; E-mail: kunkel@niehs.nih.gov
* These authors contributed equally to this work
† Present address: Department of Pharmacological Sciences, SUNY at Stony Brook, Stony Brook, New York, USA
Received 19 November 2007; Accepted 30 January 2008; Published online 28 March 2008.
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Abstract
The simple deletion of nucleotides is common in many organisms. It can be advantageous when it activates genes beneficial to microbial survival in adverse environments, and deleterious when it mutates genes relevant to survival, cancer or degenerative diseases. The classical idea is that simple deletions arise by strand slippage. A prime opportunity for slippage occurs during DNA synthesis, but it remains unclear how slippage is controlled during a polymerization cycle. Here, we report crystal structures and molecular dynamics simulations of mutant derivatives of DNA polymerase bound to a primer–template during strand slippage. Relative to the primer strand, the template strand is in multiple conformations, indicating intermediates on the pathway to deletion mutagenesis. Consistent with these intermediates, the mutant polymerases generate single-base deletions at high rates. The results indicate that dNTP-induced template strand repositioning during conformational rearrangements in the catalytic cycle is crucial to controlling the rate of strand slippage.
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