Figure 1. Model for mitotic inheritance of persistent G-quadruplexes.

The upper illustration (dashed box) visualizes a replication-blocking G-quadruplex causing a ssDNA gap across the G-quadruplex-containing strand. In case quadruplexes are formed in the lagging strand, dsDNA 5′ to the G-quadruplex may mark the previously deposited Okazaki fragment. In case G-quadruplexes are formed during leading strand synthesis, dsDNA 5′ to the G-quadruplex may be the product of restart of replication downstream of the obstruction, or of an Okazaki fragment from a converging fork. 1. Mitotic inheritance of a stable G-quadruplex, paired with a gapped DNA strand, allows cycles of mutagenesis among proliferating cells (see step 2–5) 2. Similar to DNA interstrand cross-links, sporadic G-quadruplexes are expected not to impede overall genome duplication or the approach of converging forks, yet constitute a potent local block to nascent strand synthesis. 3. Failed replication of the G-quadruplex will generate a small ssDNA gap in the nascent strand, creating the pre-mutagenic lesion similar to the one before S-phase. However, replication of the gapped parental strand (heretofore located opposite the G-quadruplex) will cause a DSB. 4. Persistence of the G-quadruplex prevents DSB repair via HR, which requires templated DNA synthesis on the sister chromatid. Instead, the DSB is repaired via TMEJ, generating a small deletion in one of the sister chromatids. The resultant deletion mirrors the position and size of the ssDNA gap previously caused by the stable G-quadruplex. 5. Mitotic separation of sister chromatids generates two daughter cells, one inheriting a deletion and one inheriting a stable G-quadruplex and a ssDNA gap on that very same locus.