Low-fidelity DNA synthesis by human DNA polymerase theta.

摘要

Human DNA polymerase theta (pol {theta} or POLQ) is a proofreading-deficient family A enzyme implicated in translesion synthesis (TLS) and perhaps in somatic hypermutation (SHM) of immunoglobulin genes. These proposed functions and kinetic studies imply that pol {theta} may synthesize DNA with low fidelity. Here, we show that when copying undamaged DNA, pol {theta} generates single base errors at rates 10- to more than 100-fold higher than for other family A members. Pol {theta} adds single nucleotides to homopolymeric runs at particularly high rates, exceeding 1% in certain sequence contexts, and generates single base substitutions at an average rate of 2.4 x 10pd, comparable to inaccurate family Y human pol (5.8 x 10pd) also implicated in TLS. Like pol , pol {theta} is processive, implying that it may be tightly regulated to avoid deleterious mutagenesis. Pol {theta} also generates certain base substitutions at high rates within sequence contexts similar to those inferred to be copied by pol {theta} during SHM of immunoglobulin genes in mice. Thus, pol {theta} is an exception among family A polymerases, and its low fidelity is consistent with its proposed roles in TLS and SHM.