InterPro domain: IPR007218

DNA polymerase delta (Pol delta) is responsible for effective DNA replication, playing a key role in the elongation of both the leading and the lagging strands of DNA and the maturation of Okazaki fragments [ 1 ]. It consists of four subunits: the catalytic and largest subunit p125, p50 that interacts with p125 to form the core enzyme, p68 which interacts with p50, and a fourth subunit, p12, that bridges p125 and p50, stabilising its interaction [ 2 , 3 ].

This entry represents the p12 subunit (also called subunit 4), which increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3' to 5' exonuclease activity in the Pol delta4 tetramer complex [ 4 , 4 , 4 ]. p12 is PCNA-binding protein, as it contains a N-terminal PCNA-binding motif. Under conditions of DNA replication stress, it is required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb [ 5 ]. This subunit is involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites [ 6 ]. p12 plays a major role in Pol delta4 catalytic functions while its degradation is required for the conversion of Pol delta4 to Pol delta3 in the cellular response to DNA damage, as Pol delta3 has an enhanced proofreading activity [ 6 ].

1. Dynamics of enzymatic interactions during short flap human Okazaki fragment processing by two forms of human DNA polymerase δ. DNA Repair (Amst.) 12, 922-35
2. Functional roles of p12, the fourth subunit of human DNA polymerase delta. J. Biol. Chem. 281, 14748-55
3. DNA damage alters DNA polymerase delta to a form that exhibits increased discrimination against modified template bases and mismatched primers. Nucleic Acids Res. 37, 647-57
4. The p12 subunit of human polymerase delta modulates the rate and fidelity of DNA synthesis. Biochemistry 49, 3545-54
5. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343, 88-91
6. Degradation of p12 subunit by CRL4Cdt2 E3 ligase inhibits fork progression after DNA damage. J. Biol. Chem. 288, 30509-14