Mechanism of somatic hypermutation at the WA motif by human DNA polymerase η

• DOI: 10.1073/pnas.1303126110
• Publication Date: 2013-04-30T04:27:35Z
• Authors: Ye Zhao; Mark T. Gregory; Christian Biertüm...; Yue-Jin Hua; Fumio Hanaoka; Wei Yang
• Keywords: Primer (cosmetics)

Somatic hypermutation is programmed base substitutions in the variable regions of Ig genes for high-affinity antibody generation. Two motifs, RGYW and WA (R, purine; Y, pyrimidine; W, A or T), have been found to be somatic hotspots. Overwhelming evidence suggests that DNA polymerase η (Pol η) responsible converting motif WG by misincorporating dGTP opposite templating T. To elucidate molecular mechanism, crystal structures kinetics human Pol substituting dATP four sequence contexts, TA, AA, GA, CA, determined compared. The T:dGTP wobble pair stabilized Gln-38 Arg-61, two uniquely conserved residues among η. Weak paring W (T:A A:T) at primer end their distinct interactions with lead misincorporation G motif. Between our kinetic structural data indicate A-to-G mutation occurs more readily TA context than AA. Finally, can extend T:G mispair efficiently complete mutagenesis.