Mismatch repair, molecular switches, and signal transduction

  1. Richard Fishel1
  1. Genetics and Molecular Biology Program, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 USA

This extract was created in the absence of an abstract.

The foundation of molecular switches in biology is grounded in translation elongation and cellular signal transduction. In these systems, guanine nucleotide-bound proteins (G proteins) produce the ON and OFF signaling states that act as gates for downstream biochemical processes. Recent studies on the human mismatch repair reaction have suggested a similar molecular switch that relies on adenine nucleotide-bound forms (A proteins) to produce an ON and OFF signaling state. In the field of signal transduction, the concept of a molecular switch is elementary whereas the biochemical processes of DNA repair appear foreign. Similarly, the field of DNA repair recognizes the complex machinery required for DNA manipulation events but regards biochemical signaling processes as essential cellular input but outside the genome juggernaut. The concept of a molecular switch as an integral step in mismatch repair should accelerate communication between these two fields toward a resolved and unified mechanism for biological signaling processes.

Genetics of mismatch repair

There are at least three ways in which mismatched nucleotides arise in DNA: (1) physical or chemical damage to the DNA and its precursors, such as deamination of 5-methyl-cytosine (Friedberg 1990); (2) misincorporation of nucleotides during DNA replication can yield mismatched base pairs as well as the insertion and deletion of nucleotides (for review, see Kolodner 1996; Modrich 1989, 1997); and (3) genetic recombination produces regions of heteroduplex DNA that may contain mismatched nucleotides when such heteroduplexes result from the pairing of two different parental DNA sequences (Holliday 1964). Mismatched nucleotides produced by each of these mechanisms are known to be repaired by enzyme systems that are both specific and overlapping (Friedberg 1990).

The most extensively studied system for mismatch repair (MMR) is the DNA adenine methylation (Dam)-instructed pathway of Escherichia coli (for review, see Modrich 1989; Modrich and Lahue 1996). The Dam-instructed pathway promotes …

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