Microhomology for priming FLT3-ITD replication slippage. (A) Misalignment and priming using germline (visible) microhomology. The recurrent c.1780-1800dup primed by TGAT microhomology (red against yellow) is shown. (B) Occult (invisible) microhomology-mediated priming, where TdT adds a base to the misaligning 3′ end. This base provides the homology for priming, but is not detected in the final sequence as it matches an existing base. The 24-bp c.1770-1793dup is shown. (C) Occult microhomology-mediated priming following addition of multiple N-nucleotides (blue). Only the terminal N-nucleotide matches the target strand, hence the previous N-nucleotides are visible as filler DNA between the 2 copies of the repeat. A 21-bp FLT3-ITD is shown (17-bp c.1764_1780 duplication, with 4 additional N-nucleotides). These models are applicable to either simple replication slippage or break-induced models of MMRDR. The latter can occur following replication across a single-stranded nick and resulting replication fork collapse; fork collapse creates a single-ended double-stranded break, and the 3′ end must invade the template strand to reinitiate replication.