Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions

DNA lesions can often block DNA replication, so cells possess specialized l ow-fidelity, and often error-prone, DNA polymerases that can bypass such le sions and promote replication of damaged DNA(1). The Saccharomyces cerevisi ae RAD30 and human hRAD30A encode Pol eta, which bypasses a cis-syn thymine -thymine dimer efficiently and accurately(2-7). Here we show that a related human gene, hRAD30B(8), encodes the DNA polymerase Pol iota, which misinco rporates deoxynucleotides at a high rate. To bypass damage, Pol iota specif ically incorporates deoxynucleotides opposite highly distorting or non-inst ructional DNA lesions. This action is combined with that of DNA polymerase Pol zeta, which is essential for damage-induced mutagenesis, to complete th e lesion bypass. Pol zeta is very inefficient in inserting deoxynucleotides opposite DNA lesions, but readily extends from such deoxynucleotides once they have been inserted. Thus, in a new model for mutagenic bypass of DNA l esions in eukaryotes, the two DNA polymerases act sequentially: Pol iota in corporates deoxynucleotides opposite DNA lesions, and Pol zeta functions as a mispair extender.