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Molecular and Cellular Biology, December 2001, p. 7995-8006, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.7995-8006.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Highly Frequent Frameshift DNA Synthesis by Human DNA Polymerase µ

Yanbin Zhang, Xiaohua Wu, Fenghua Yuan, Zhongwen Xie, and Zhigang Wang*

Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536

Received 11 April 2001/Returned for modification 24 May 2001/Accepted 28 August 2001

DNA polymerase µ (Polµ) is a newly identified member of the polymerase X family. The biological function of Polµ is not known, although it has been speculated that human Polµ may be a somatic hypermutation polymerase. To help understand the in vivo function of human Polµ, we have performed in vitro biochemical analyses of the purified polymerase. Unlike any other DNA polymerases studied thus far, human Polµ catalyzed frameshift DNA synthesis with an unprecedentedly high frequency. In the sequence contexts examined, -1 deletion occurred as the predominant DNA synthesis mechanism opposite the single-nucleotide repeat sequences AA, GG, TT, and CC in the template. Thus, the fidelity of DNA synthesis by human Polµ was largely dictated by the sequence context. Human Polµ was able to efficiently extend mismatched bases mainly by a frameshift synthesis mechanism. With the primer ends, containing up to four mismatches, examined, human Polµ effectively realigned the primer to achieve annealing with a microhomology region in the template several nucleotides downstream. As a result, human Polµ promoted microhomology search and microhomology pairing between the primer and the template strands of DNA. These results show that human Polµ is much more prone to cause frameshift mutations than base substitutions. The biochemical properties of human Polµ suggest a function in nonhomologous end joining and V(D)J recombination through its microhomology searching and pairing activities but do not support a function in somatic hypermutation.

* Corresponding author. Mailing address: 306 Health Sciences Research Bldg., Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536. Phone: (859) 323-5784. Fax: (859) 323-1059. E-mail: zwang{at}pop.uky.edu.

Molecular and Cellular Biology, December 2001, p. 7995-8006, Vol. 21, No. 23
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.23.7995-8006.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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