Photo of R. Michael Liskay, Ph.D.

R. Michael Liskay Ph.D.

  • (503) 494-3475

We use yeast and mice to study DNA mismatch repair (MMR), which corrects mismatches and senses DNA damage. MMR gene mutations increase spontaneous mutation and predispose to hereditary and sporadic cancer.  Using gene targeting strategies, we derive and study knockout mice for four MutL homologs, Mlh1, Pms1 or Pms2, and Mlh3. We have observed increased mutation and cancer risk in these animals, although the severity varies between the different knockouts. In a related project, we have developed an assay using the site-specific recombinase Cre to stochastically inactivate tumor suppressor genes or activate oncogenes in the mouse. The system also uses a color marker (B-galactosidase) which is activated by the recombinase thus marking those cell lineages experiencing inactivation (or activation) of the "loxp"-tagged tumor suppressors/oncogenes. One question being addressed is "What is the minimum number of cancer gene alterations that are sufficient to promote intestinal tumor formation and progression in the mouse?" Our studies in yeast are centered on a better understanding of the mechanism and gene products involved in DNA mismatch repair.

Education

  • Ph.D., University of Washington, Seattle Washington 1975

Memberships and associations

  • American Association for the Advancement of Science (Fellow), Genetics Society of America

Publications

  • "Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation." Proceedings of the National Academy of Sciences of the United States of America  In: , Vol. 113, No. 43, 25.10.2016, p. 12192-12197.
  • "An intact Pms2 ATPase domain is not essential for male fertility." DNA Repair  In: , Vol. 39, 01.03.2016, p. 46-51.
  • "Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention." Carcinogenesis  In: , Vol. 35, No. 1, 01.2014, p. 237-246.
  • "Different phenotypic consequences of simultaneous versus stepwise Apc loss." Oncogene In: , Vol. 31, No. 16, 19.04.2012, p. 2028-2038.
  • "Conservation of functional asymmetry in the mammalian MutLα ATPase." DNA Repair  In: , Vol. 9, No. 11, 10.11.2010, p. 1209-1213.
  • "Embryonic lethality after combined inactivation of Fancd2 and Mlh1 in Mice." Cancer Research  In: , Vol. 69, No. 24, 15.12.2009, p. 9431-9438.
  • "Tractable Cre-lox system for stochastic alteration of genes in mice." Nature Methods  In: , Vol. 5, No. 3, 03.2008, p. 227-229.
  • "A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair." DNA Repair  In: , Vol. 6, No. 11, 01.11.2007, p. 1572-1583.
  • "Mutations affecting a putative MutLα endonuclease motif impact multiple mismatch repair functions." DNA Repair  In: , Vol. 6, No. 10, 01.10.2007, p. 1463-1470.
  • "Involvement of deoxycytidylate deaminase in the response to Sn1-type methylation DNA damage in budding yeast." Current Biology  In: , Vol. 17, No. 17, 04.09.2007.
  • "The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair." Cancer Letters In: , Vol. 249, No. 2, 08.05.2007, p. 148-156.
  • "Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance." Cancer Letters In: , Vol. 244, No. 2, 08.12.2006, p. 195-202.
  • "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6." Carcinogenesis In: , Vol. 27, No. 12, 12.2006, p. 2402-2408.
  • "Crossover and noncrossover pathways in mouse meiosis." Molecular Cell  In: , Vol. 20, No. 4, 23.11.2005, p. 563-573.
  • "Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I." Journal of Cell Biology In: , Vol. 171, No. 3, 07.11.2005, p. 447-458.
  • "Novel PMS1 alleles preferentially affect the repair of primer strand loops during DNA replication." Molecular and Cellular Biology  In: , Vol. 25, No. 21, 11.2005, p. 9221-9231.
  • "Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse." Cancer Research In: , Vol. 65, No. 19, 01.10.2005, p. 8662-8670.
  • "EXO1-A multi-tasking eukaryotic nuclease." DNA Repair  In: , Vol. 3, No. 12, 02.12.2004, p. 1549-1559.
  • "Apoptosis and mutation in the murine small intestine : Loss of Mlh1- and Pms2-dependent apoptosis leads to increased mutation in vivo." DNA Repair In: , Vol. 2, No. 9, 18.09.2003, p. 1029-1039.
  • "Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice." Oncogene In: , Vol. 22, No. 29, 17.07.2003, p. 4581-4585.
  • "Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type." Human Genetics  In: , Vol. 112, No. 2, 02.2003, p. 117-123.
  • "Diet, cancer and aging in DNA mismatch repair deficient mice." Carcinogenesis  In: , Vol. 23, No. 11, 01.11.2002, p. 1807-1810.
  • "Characterization of nuclease-dependent functions of Exo1p in Saccharomyces cerevisiae." DNA Repair  In: , Vol. 1, No. 11, 01.11.2002, p. 895-912.
  • "Alleles of the yeast PMS1 mismatch-repair gene that differentially affect recombination- and replication-related processes." Genetics  In: , Vol. 162, No. 3, 01.11.2002, p. 1131-1145.
  • "Contribution of human Mlh1 and Pms2 ATPase activities to DNA mismatch repair." Journal of Biological Chemistry  In: , Vol. 277, No. 24, 14.06.2002, p. 21801-21809.
  • "Evidence for the lack of mismatch-repair directed antirecombination during mouse meiosis." Journal of Heredity  In: , Vol. 93, No. 3, 05.2002, p. 201-205.
  • "Maternal effect for DNA mismatch repair in the mouse." Genetics In: , Vol. 160, No. 1, 2002, p. 271-277.
  • "Interactions of Exo1p with components of MutLα in Saccharomyces cerevisiae." Proceedings of the National Academy of Sciences of the United States of America In: , Vol. 98, No. 17, 14.08.2001, p. 9760-9765.
  • "Hypermutability to ionizing radiation in mismatch repair-deficient, Pms2 knockout mice." Cancer Research In: , Vol. 61, No. 9, 01.05.2001, p. 3775-3780.
  • "MSH-MLH complexes formed at a DNA mismatch are disrupted by the PCNA sliding clamp." Journal of Molecular Biology  In: , Vol. 306, No. 5, 09.03.2001, p. 957-968.

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