Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 20, Pages 8146-8151Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303126110
Keywords
pi-cation stacking; A-to-G transition; immunoglobulin
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
- Chinese Ministry of Education
- National Natural Science Foundation of China [31210103904]
- Ministry of Education (KAKENHI)
- Grants-in-Aid for Scientific Research [22131001, 22249005, 22131008] Funding Source: KAKEN
Ask authors/readers for more resources
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 hypermutation hotspots. Overwhelming evidence suggests that DNA polymerase eta (Pol eta) is responsible for converting the WA motif to WG by misincorporating dGTP opposite the templating T. To elucidate the molecular mechanism, crystal structures and kinetics of human Pol eta substituting dGTP for dATP in four sequence contexts, TA, AA, GA, and CA, have been determined and compared. The T: dGTP wobble base pair is stabilized by Gln-38 and Arg-61, two uniquely conserved residues among Pol eta. Weak base paring of the W (T:A or A:T) at the primer end and their distinct interactions with Pol eta lead to misincorporation of G in the WA motif. Between two WA motifs, our kinetic and structural data indicate that A-to-G mutation occurs more readily in the TA context than AA. Finally, Pol eta can extend the T:G mispair efficiently to complete the mutagenesis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available