Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 30, Pages 13384-13389Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1008589107
Keywords
DNA mismatch repair; B cell lymphoma; class switch recombination; somatic hypermutation; spermatogenesis
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Funding
- Netherlands Organization for Scientific Research
- Spanish Ministry of Education and Science [EX-2006-0732]
- National Institutes of Health [GM45190, CA72649, CA102705, CA76329, CA93484]
- National Women's Division of the Albert Einstein College of Medicine
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The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2(E702K) knock-in mice. Pms2(EK/EK) mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in Pms2(EK/EK) B cells, indicating a specific role in Ig diversity. In contrast to Pms2(-/-) mice, Pms2(EK/EK) male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression.
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