Inhibition of DNA synthesis facilitates expansion of low-complexity repeats: Is strand slippage stimulated by transient local depletion of specific dNTPs?

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Abstract

Simple DNA repeats (trinucleotide repeats, micro- and minisatellites) are prone to expansion/contraction via formation of secondary structures during DNA synthesis. Such structures both inhibit replication forks and create opportunities for template-primer slippage, making these repeats unstable. Certain aspects of simple repeat instability, however, suggest additional mechanisms of replication inhibition dependent on the primary DNA sequence, rather than on secondary structure formation. I argue that expanded simple repeats, due to their lower DNA complexity, should transiently inhibit DNA synthesis by locally depleting specific DNA precursors. Such transient inhibition would promote formation of secondary structures and would stabilize these structures, facilitating strand slippage. Thus, replication problems at simple repeats could be explained by potentiated toxicity, where the secondary structure-driven repeat instability is enhanced by DNA polymerase stalling at the low complexity template DNA.

This minireview is dedicated to the FASEB-2012 meeting “Dynamic DNA Structures in Biology”, organized by Nancy Maizels and Sergei Mirkin.

Expanded trinucleotide repeats are inherently unstable due to their propensity for strand slippage. I hypothesize that strand slippage is further promoted by local transient depletion of specific dNTPs during synthesis across this low-complexity DNA. Possible hairpin extrusion between polymerase and the clamp (the scheme) may explain saltatory repeat expansion.

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