The human genome encodes multiple enzymes that are capable of synthesizing DNA.[1] In hindsight, it seems obvious that the complex nature of nucleic acid chemistry would necessitate a redundancy of polymerase activity that does not rely upon one single enzyme for nucleotide selectivity.[2, 3] Accuracy during replication of the genetic code is vital to multi-cellular organisms, but the molecular constraints that facilitate high-fidelity DNA synthesis often prove inhibitory in the face of adducted (i.e. “damaged”) DNA.[4, 5] Evolution has resulted in many non-essential DNA polymerases, including the Y-family, that are conserved as a means of bypassing damaged DNA and/or unusual secondary structures in the template DNA.[6] The deregulation of Y-family members has been associated with several tumor types, including breast, ovarian, colorectal and non-small cell lung cancers.[7-11] Moreover, germline mutations in the human gene encoding polymerase η result in Xeroderma pigmentosum variant type (XPV), which is characterized by a high susceptibility to skin cancer.[12, 13]
