DNA Mismatch Repair May or May Not Participate in Small Repeat Length Changes During Replication in Dividing Cells or During Gap Repair in Nondividing Cells

As discussed already, the ability to form hairpins of various degrees of stability, coupled with the potential for replication slippage within direct repeats, certainly contributes, in a major way, to the potential for variation in the length of triplet and possibly other types of repeats. d(CTG)n, d(CAG)n, d(CGG) n, and d(CCG)n repeats form hairpins with a GC ■ GC dinucleotide interspersed with a T ■ T, A ■ A, G ■ G, or C ■ C mismatch, respectively (Fig. 1, panels A.1, A.2). The involvement of mismatch repair in repeat instability in E. coli has recently been reviewed (Parniewski and Staczek 2002). The stability of these hairpins decreases in the order listed. As discussed already, human mismatch repair proteins bind to d(CAG)n hairpins better than to d(CTG)n hairpins (Pearson et al. 1997; Owen et al. 2005). DNA mismatch repair systems are designed to recognize noncanonical base pairs or mismatches following errors in DNA replication and repair them in the nascent strand when not corrected by polymerase proofreading activities. Traditionally, mismatch repair activities are thought to operate in dividing cells that are actively undergoing DNA replication. Interestingly, mice deficient in mismatch repair proteins show reduced rates of repeat instability (Manley et al.

Fig. 5 Gap repair associated with expansion, deletion, or DNA repair. A Gap repair with expansion. Strand displacement synthesis at a nick leads to a flap that is normally digested by the flap nuclease FEN-1 (step 2). However, the formation of a hairpin or other DNA secondary structure can interfere with digestion (step 3). The hairpin may be stabilized by Msh2-Msh3 and subsequent ligation would lead to expansion in the nascent strand (step 4). If the hairpin escapes subsequent mismatch repair, nucleotide excision-type repair, or other repair events, it will lead to expansion in one DNA molecule upon the next round of replication (step 5). B Gap repair with deletion. If a hairpin-forming sequence is present within a gap that may be formed during repair of spontaneous or extraneous DNA damage, it may fold into a hairpin (step 2). Slipped misalignment across a hairpin during DNA replication would lead to the loss of repeats in the nascent strand (step 3), which would lead to deletion in one DNA molecule following the next round of replication (step 4)

Fig. 5 Gap repair associated with expansion, deletion, or DNA repair. A Gap repair with expansion. Strand displacement synthesis at a nick leads to a flap that is normally digested by the flap nuclease FEN-1 (step 2). However, the formation of a hairpin or other DNA secondary structure can interfere with digestion (step 3). The hairpin may be stabilized by Msh2-Msh3 and subsequent ligation would lead to expansion in the nascent strand (step 4). If the hairpin escapes subsequent mismatch repair, nucleotide excision-type repair, or other repair events, it will lead to expansion in one DNA molecule upon the next round of replication (step 5). B Gap repair with deletion. If a hairpin-forming sequence is present within a gap that may be formed during repair of spontaneous or extraneous DNA damage, it may fold into a hairpin (step 2). Slipped misalignment across a hairpin during DNA replication would lead to the loss of repeats in the nascent strand (step 3), which would lead to deletion in one DNA molecule following the next round of replication (step 4)

1999; Kovtun and McMurray 2001; van Den Broek et al. 2002; Watase et al. 2003; Savouret et al. 2003, 2004; Wheeler et al. 2003; Gomes-Pereira et al. 2004). These proteins have also been suggested to participate in repair of spontaneous or endogenous DNA damage in quiescent cells, even in sperm (Kovtun and McMurray 2001; McMurray and Kortun 2003; Kovtun et al. 2004).

In nondividing cells, mismatch repair proteins have been implicated in small repeat length changes, where it has been proposed they participate in the stabilization of slipped, hairpin-containing structures formed during gap repair (Fig. 5) that may be associated with spontaneous DNA damage (Kovtun and McMurray 2001; McMurray and Kortun 2003; Kovtun et al. 2004). A recent demonstration of inhibition of enzymatic activity of the Msh2-Msh3 heterodimer when bound to d(CAG)n hairpins is consistent with recognition, binding, and stabilization of loopouts that then could be ligated into an expansion event (Owen et al. 2005). Panigrahi et al. (2005), however, recently demonstrated clearly that d(CAG)n and d(CTG)n loopouts can be repaired in an orientation- and sequence-dependent fashion although mismatch repair proteins may not be involved.

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