Aberrant chromatin resolution in G2/M leads to chromosome instability

Interphase to mitosis transition is integral to cellular life and requires extensive large-scale chromatin remodelling. Cells coordinate compaction but recurrent cytogenetic lesions appear at common fragile sites (CFSs) in a tissue-specific manner following replication stress, marking regions of genome instability in cancer. Current views suggest lesion formation is dependent on late replication, but instead we report that replication stress causes changes in replication dynamics and origin firing efficiency. We show that CFSs are characterised by impaired compaction, manifested either as cytogenetic abnormalities or as disrupted mitotic figures on cytogenetically normal chromosomes. Chromosome condensation assays reveal that compaction-resistant chromatin lesions persist at CFSs throughout the cell cycle, due to faulty condensin loading at CFS region and a defect in condensin I mediated compaction. Our data supports a model for CFS formation where aberrant replication dynamics lead to faulty condensin I recruitment and mitotic misfolding, mitotic DNA synthesis, and subsequent chromosomal instability.