Figure 4. APOBEC-induced transient hyper-mutation during cancer evolution.

(middle) Generation of isolated persistent single stranded DNA regions (e.g. a resected DSB) are targets for APOBEC cytidine deamination (stars) resulting in clustered mutations (mutations are depicted as spheres: C = red, G = green, A = blue and T = yellow). Individual clusters can inactivate a single tumor suppressor gene, activate an oncogene (e.g. oncogenic Ras: “O-Ras”), or alter transcriptional profiles by modifying microRNAs or transcription factor expression. Additional genetic alterations accumulated during subsequent cell divisions lead to cancer progression. (left) Multiple viral infections may each transiently induce APOBEC activity resulting in waves of APOBEC signature mutations that ultimately lead to dis-regulated cell proliferation. (right) Formation of multiple ssDNA regions in a cell, as occurs during oncogene-induced replication stress, allows APOBEC-induced mutagenesis to inactivate multiple cancer genes simultaneously including those responsible of proliferative barriers that can hold pre-cancerous cells in a senescent state (e.g. TP53, ATM).