(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).