The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair

Suzanne M. Deschênes; Guy Tomer; Megan Nguyen; Naz Erdeniz; Nicole C. Juba; Natalia Sepúlveda; Jenna E. Pisani; R. Michael Liskay

doi:10.1016/j.canlet.2006.08.008

The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair

Suzanne M. Deschênes, Guy Tomer, Megan Nguyen, Naz Erdeniz, Nicole C. Juba, Natalia Sepúlveda, Jenna E. Pisani, R. Michael Liskay

Molecular and Medical Genetics

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

The hPMS2 mutation E705K is associated with Turcot syndrome. To elucidate the pathogenesis of hPMS2-E705K, we modeled this mutation in yeast and characterized its expression and effects on mutation avoidance in mammalian cells. We found that while hPMS2-E705K (pms1-E738K in yeast) did not significantly affect hPMS2 (Pms1p in yeast) stability or interaction with MLH1, it could not complement the mutator phenotype in MMR-deficient mouse or yeast cells. Furthermore, hPMS2-E705K/pms1-E738K inhibited MMR in wild-type (WT) mammalian cell extracts or yeast cells only when present in excess amounts relative to WT PMS2. Our results strongly suggest that hPMS2-E705K is a recessive loss-of-function allele.

Original language	English (US)
Pages (from-to)	148-156
Number of pages	9
Journal	Cancer Letters
Volume	249
Issue number	2
DOIs	https://doi.org/10.1016/j.canlet.2006.08.008
State	Published - May 8 2007

Keywords

Mismatch repair
PMS2
Turcot syndrome

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2006.08.008

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title = "The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair",

abstract = "The hPMS2 mutation E705K is associated with Turcot syndrome. To elucidate the pathogenesis of hPMS2-E705K, we modeled this mutation in yeast and characterized its expression and effects on mutation avoidance in mammalian cells. We found that while hPMS2-E705K (pms1-E738K in yeast) did not significantly affect hPMS2 (Pms1p in yeast) stability or interaction with MLH1, it could not complement the mutator phenotype in MMR-deficient mouse or yeast cells. Furthermore, hPMS2-E705K/pms1-E738K inhibited MMR in wild-type (WT) mammalian cell extracts or yeast cells only when present in excess amounts relative to WT PMS2. Our results strongly suggest that hPMS2-E705K is a recessive loss-of-function allele.",

keywords = "Mismatch repair, PMS2, Turcot syndrome",

author = "Desch{\^e}nes, {Suzanne M.} and Guy Tomer and Megan Nguyen and Naz Erdeniz and Juba, {Nicole C.} and Natalia Sep{\'u}lveda and Pisani, {Jenna E.} and {Michael Liskay}, R.",

note = "Funding Information: We gratefully acknowledge Sandy Dudley for expert technical assistance, and Dr. Andrew Buermeyer for helpful comments. This work was supported by grants to S.M. Desch{\^e}nes (NIH F32 CA79200-03; University Research and Creativity Grants, Sacred Heart Univ.), N. Erdeniz (NIH GM045413), G. Tomer (Human Frontier Science Program Fellowship), and R.M. Liskay (NIH GM032741).",

year = "2007",

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doi = "10.1016/j.canlet.2006.08.008",

language = "English (US)",

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T1 - The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair

AU - Deschênes, Suzanne M.

AU - Tomer, Guy

AU - Nguyen, Megan

AU - Erdeniz, Naz

AU - Juba, Nicole C.

AU - Sepúlveda, Natalia

AU - Pisani, Jenna E.

AU - Michael Liskay, R.

N1 - Funding Information: We gratefully acknowledge Sandy Dudley for expert technical assistance, and Dr. Andrew Buermeyer for helpful comments. This work was supported by grants to S.M. Deschênes (NIH F32 CA79200-03; University Research and Creativity Grants, Sacred Heart Univ.), N. Erdeniz (NIH GM045413), G. Tomer (Human Frontier Science Program Fellowship), and R.M. Liskay (NIH GM032741).

PY - 2007/5/8

Y1 - 2007/5/8

N2 - The hPMS2 mutation E705K is associated with Turcot syndrome. To elucidate the pathogenesis of hPMS2-E705K, we modeled this mutation in yeast and characterized its expression and effects on mutation avoidance in mammalian cells. We found that while hPMS2-E705K (pms1-E738K in yeast) did not significantly affect hPMS2 (Pms1p in yeast) stability or interaction with MLH1, it could not complement the mutator phenotype in MMR-deficient mouse or yeast cells. Furthermore, hPMS2-E705K/pms1-E738K inhibited MMR in wild-type (WT) mammalian cell extracts or yeast cells only when present in excess amounts relative to WT PMS2. Our results strongly suggest that hPMS2-E705K is a recessive loss-of-function allele.

AB - The hPMS2 mutation E705K is associated with Turcot syndrome. To elucidate the pathogenesis of hPMS2-E705K, we modeled this mutation in yeast and characterized its expression and effects on mutation avoidance in mammalian cells. We found that while hPMS2-E705K (pms1-E738K in yeast) did not significantly affect hPMS2 (Pms1p in yeast) stability or interaction with MLH1, it could not complement the mutator phenotype in MMR-deficient mouse or yeast cells. Furthermore, hPMS2-E705K/pms1-E738K inhibited MMR in wild-type (WT) mammalian cell extracts or yeast cells only when present in excess amounts relative to WT PMS2. Our results strongly suggest that hPMS2-E705K is a recessive loss-of-function allele.

KW - Mismatch repair

KW - PMS2

KW - Turcot syndrome

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The E705K mutation in hPMS2 exerts recessive, not dominant, effects on mismatch repair

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