DNA Mismatch Repair and its Role in Huntington's Disease

Abstract

DNA mismatch repair (MMR) is a highly conserved genome stabilizing pathway that corrects DNA replication errors, limits chromosomal rearrangements, and mediates the cellular response to many types of DNA damage. Counterintuitively, MMR is also involved in the generation of mutations, as evidenced by its role in causing somatic triplet repeat expansion in Huntington's disease (HD) and other neurodegenerative disorders. In this review, we discuss the current state of mechanistic knowledge of MMR and review the roles of key enzymes in this pathway. We also present the evidence for mutagenic function of MMR in CAG repeat expansion and consider mechanistic hypotheses that have been proposed. Understanding the role of MMR in CAG expansion may shed light on potential avenues for therapeutic intervention in HD.

Keywords: DNA mismatch repair; DNA structures; Huntington’s disease; neurodegeneration; somatic expansion; triplet repeat instability.

Fig. 1

Mechanisms of 5′ and 3′ human mismatch repair. Distinct molecular mechanisms mediate mismatch repair, depending on strand-break polarity. Left, DNA mismatches or extrahelical extrusions are recognized by MutSα or MutSβ. When the strand-break is located 5′ to the mismatch, MutSα/β activates the processive 5′–3′ exonuclease activity of ExoI in an ATP-dependent manner. The ensuing gap is protected by the single-stranded DNA binding protein complex RPA, followed by DNA resynthesis across the gap by DNA polymerase δ, aided by the replication sliding clamp PCNA and the clamp loader RFC. Right, if the strand-break is located 3′ to the mispair, error correction relies on oriented loading of PCNA by RFC at the strand break. Thus, MutSα/β recruits MutLα in an ATP-dependent manner, resulting in the activation of a latent endonuclease function in MutLα in the presence of DNA-loaded PCNA. The additional strand-breaks catalyzed by MutLα bracket the mismatch, and facilitate processive 5′–3′ hydrolysis of the nicked strand by MutSα-activated ExoI. Gap protection and filling occur as in the 5′ nick-directed reaction.

Fig. 2

Models for involvement of mismatch repair in CAG/CTG repeat expansion. Strand slippage within long repetitive CAG/CTG tracts results in the formation of extrahelical extrusions that are not only recognized by MutSβ, but also serve as loading sites for PCNA even in the absence of strand-breaks. PCNA, a ring shaped homotrimeric protein with two distinct faces (inset, indicated in green and brown) preferentially associates with its partner proteins via residues on one face. Although the two faces of PCNA are functionally non-equivalent, due to the symmetry of the extrahelical extrusions, PCNA loading at such structures occurs in both possible spatial orientations. Since the strand directionality of the MutSβ-dependent activity of the MutLα endonuclease is determined by the orientation of DNA-loaded PCNA, the disoriented loading of PCNA misdirects MutLα catalyzed incisions to either DNA strand. Left, when incision occurs on the extrusion-containing strand (shown in blue), strand excision results in removal of the extrusion, and faithful repair by Polδ results in a contraction (not shown). However, error-prone gap resynthesis by Polη or Polβ as illustrated in the diagram may provide additional opportunities for strand slippage and formation of new extrahelical extrusions, which either result in a net increase in CAG repeat length (i.e., expansion) or trigger additional rounds of MutSβ-initiated incision/excision. Middle, when MutLα-mediated strand-breaks are formed on the complementary (red) strand, error-free resynthesis by Polδ results in inclusion of the extrusion, leading to a net increase in CAG repeat length (expansion). Gap resynthesis may also be driven by Polβ as on left, resulting in additional strand slippage (not shown). Right, extrusion-bound MutSβ can also activate MutLγ in a PCNA-independent manner. The incisions catalyzed by MutLγ are restricted to the complementary (red) strand opposite to the extrusion. DNA resynthesis results in inclusion of the extrusion, leading to a net increase in CAG repeat length (expansion).