Effect of repeat instability on cancer and neurological diseases

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In eulcaryotic cells, DNA polymerase a(pol a)initiates DNA synthesis at replication origins and at the 5'-ends of Okazaki fragments. Pol a lacks proofreading activity for correcting nucleotide misincorporation errors, but it extends mismatched 31-termini inefficiently. This can lead to premature termination of mismatched/misaligned DNA primers. The mutator polymerase L868F pol a catalyzes nucleotide misincorporation and misextension more frequently than wild type pol a. We have shown misaligned primers, but not the mismatched primers, generated by pol a can be extended by pol C in a reaction that requires PCNA. A yeast strain carrying L868F or L868M allele of pol a generated +1 frameshifts at a high rate, and this rate was decreased in strains lacking the catalytic subunit of pol C. Mutations were dependent on PCNA Lys164, and were downstream of the RAD18. Furthermore, inactivation of pol S exonuclease increased the proportion of pol t -dependent +1 frameshifts. These data suggest that PCNA and pol t cooperate in a replication error promoting pathway that may be targeted to misalignment errors. In this context, pol a PCNA-, and pol C -dependent DNA synthesis may be a source of genetic variation which drives evolution or a source of mutations with potential to cause dysfunction and disease