FORK-LIKE DNA TEMPLATES SUPPORT BYPASS REPLICATION OF LESIONS THAT BLOCK DNA-SYNTHESIS ON SINGLE-STRANDED TEMPLATES

DNA replication is an asymmetric process involving concurrent DNA synt hesis on leading and lagging strands. Leading strand synthesis proceed s concomitantly with fork opening, whereas synthesis of the lagging st rand essentially takes place on a single-stranded template, The effect of this duality on DNA damage processing by the cellular replication machinery was tested using eukaryotic cell extracts and model DNA subs trates containing site-specific DNA adducts formed by the anticancer d rug cisplatin or by the carcinogen N-2-acetylaminofluorene. Bypass of both lesions was observed only with fork-like substrate, whereas compl ete inhibition of DNA synthesis occurred on damaged single-stranded DN A substrates. These results suggest a role for additional accessory fa ctors that permit DNA polymerases to bypass lesions when present in fo rk-like DNA.