Fig. 5.

Model for epigenetic instability caused by replication arrest. Leading strand replication is arrested by e.g. a G-quadruplex DNA in REV1-deficient cells [133]. i This leads to uncoupling of leading and lagging strand synthesis and the restart of leading strand replication downstream of the block (ii). Excess parental H3/H4, displaced by the helicase, is buffered by ASF1 as in Fig. 4. The stalling structure is resolved and resulting single strand gap filled in at a later stage, which crucially is remote from a supply of parental histones displaced ahead of the replicative helicase. Thus, chromatinisation of the gap is carried out only with newly synthesised histone lacking any parental modifications. These histones lack repressive modifications and allow RNA PolII access for transcription. The model proposes that loss of modifications is reinforced by the repeated replication arrest at the same structure [133]