Fig. 6: Model of how FAN1 nuclease activity might prevent repeat expansions. | Nature Neuroscience

Fig. 6: Model of how FAN1 nuclease activity might prevent repeat expansions.

From: Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset

Fig. 6

The fully base-paired (CAG)•(CTG) tract is in dynamic equilibrium with a four-way junction that includes loop-outs of (CAG)n and (CTG)n on their respective strands. Under normal cellular conditions, most repeats are in their native double-stranded conformation. However, when a longer repeat tract (>35 CAG) is present, it can adopt a more stable four-way structure that can be further bound and stabilized by MSH2/MSH3 (MutSβ) (1). This four-way junction can be cleaved on both strands in either of two orientations (A or B) by MutL complexes (2). The resulting DNA products have long overhangs, either 3′ (A) or 5′ (B), and they can either anneal fully to re-form the starting genomic DNA with no change in repeat tract length (top) or they can slip before partial reannealing (3). Slipped products can have 5′ or 3′ flaps, and these are a substrate for FAN1 nuclease cleavage (bold arrows) and subsequent ligation, yielding repeat contractions (4a). Alternatively, the slipped products can have gaps, and these are substrates for gap-filling DNA polymerases, with subsequent ligation yielding repeat expansions (4b).

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