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  • Original Paper
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Mlh1 mediates tissue-specific regulation of mitotic recombination

Oncogene volume 23, pages 9017–9024 (2004)Cite this article

Abstract

Mitotic recombination (MR) between chromosome homologs in somatic cells is a major pathway to the loss of heterozygosity (LOH), which may cause cancer if tumor suppressor genes are involved. MR can be suppressed by DNA sequence heterology (homeology) in hybrid mice from matings between species or between subspecies. We now report that MR is relatively suppressed in F1 hybrids between inbred strains C57BL/6 and 129S2. The frequency of MR in fibroblasts is lower in F1 hybrid mice than in either of the two parental strains. However, MR in T cells is not affected by strain background. Thus, relatively small genetic differences are capable of restricting MR in a tissue-specific manner. Using Mlh1-deficient mice, we tested the role of mismatch repair in MR in two isogenic cell types. In fibroblasts of C57BL/6 × 129S2 F1 mice, the suppression of MR is alleviated in the absence of MLH1. In contrast, MR is not affected by Mlh1 status in T cells. The frequency of point mutations at the reporter gene loci Aprt and Hprt, on the other hand, is significantly increased in both T cells and fibroblasts of Mlh1−/− mice. Thus, different cell types respond differently to MLH1 deficiency, and the contribution of MR to tumorigenesis may be tissue-dependent in the absence of mismatch repair.

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References

  • Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC and White RL . (1983). Nature, 305, 779–784.

  • Cervantes RB, Stringer JR, Shao C, Tischfield JA and Stambrook PJ . (2002). Proc. Natl. Acad. Sci. USA, 99, 3586–3590.

  • Datta A, Adjiri A, New L, Crouse GF and Jinks-Robertson S . (1996). Mol. Cell. Biol., 16, 1085–1093.

  • DeBerardinis RJ, Goodier JL, Ostertag EM and Kazazian HH . (1998). Nat. Genet., 20, 288–290.

  • de Wind N, Dekker M, Berns A, Radman M and te Riele H . (1995). Cell, 82, 321–330.

  • Dietrich WF, Miller JC, Steen RG, Merchant M, Damron D, Nahf R, Gross A, Joyce DC, Wessel M, Dredge RD, Marquis A, Stein LD, Goodman N, Page DC and Lander ES . (1994). Nat. Genet., 7, 220–245.

  • Edelmann W, Cohen PE, Kane M, Lau K, Morrow B, Bennett S, Umar A, Kunkel T, Cattoretti G, Chaganti R, Pollard JW, Kolodner RD and Kucherlapati R . (1996). Cell, 85, 1125–1134.

  • Edelmann W, Yang K, Kuraguchi M, Heyer J, Lia M, Kneitz B, Fan K, Brown AM, Lipkin M and Kucherlapati R . (1999). Cancer Res., 59, 1301–1307.

  • Elliott B and Jasin M . (2001). Mol. Cell. Biol., 21, 2671–2682.

  • Engle SJ, Stockelman MG, Chen J, Boivin G, Yum MN, Davies PM, Ying MY, Sahota A, Simmonds HA, Stambrook PJ and Tischfield JA . (1996). Proc. Natl. Acad. Sci. USA, 93, 5307–5312.

  • Haigis KM, Caya JG, Reichelderfer M and Dove WF . (2002). Proc. Natl. Acad. Sci. USA, 99, 8927–8931.

  • Haigis KM and Dove WF . (2003). Nat. Genet., 33, 33–39.

  • Hall MC, Shcherbakova PV, Fortune JM, Borchers CH, Dial JM, Tomer KB and Kunkel TA . (2003). Nucleic Acids Res., 31, 2025–2034.

  • Harfe BD and Jinks-Robertson S . (2000). Annu. Rev. Genet., 34, 359–399.

  • Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA and Baylin SB . (1998). Proc. Natl. Acad. Sci. USA, 95, 6870–6875.

  • Huang J, Papadopoulos N, McKinley AJ, Farrington SM, Curtis LJ, Wyllie AH, Zheng S, Willson JK, Markowitz SD, Morin P, Kinzler KW, Vogelstein B and Dunlop MG . (1996). Proc. Natl. Acad. Sci. USA, 93, 9049–9054.

  • Kuraguchi M, Edelmann W, Yang K, Lipkin M, Kucherlapati R and Brown AM . (2000). Oncogene, 19, 5755–5763.

  • Liang L, Shao C, Deng L, Mendonca MS, Stambrook PJ and Tischfield JA . (2002). Mutat. Res., 502, 69–80.

  • Loeb LA . (1991). Cancer Res., 51, 3075–3079.

  • Luo G, Santoro IM, McDaniel LD, Nishijima I, Mills M, Youssoufian H, Vogel H, Schultz RA and Bradley A . (2000). Nat. Genet., 26, 424–429.

  • Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW and Vogelstein B . (1995). Science, 268, 1336–1338.

  • Mohindra A, Hays LE, Phillips EN, Preston BD, Helleday T and Meuth M . (2002). Hum. Mol. Genet., 11, 2189–2200.

  • Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA and Nikiforov YE . (2000). Science, 290, 138–141.

  • Peltomaki P and Vasen HF . (1997). Gastroenterology, 113, 1146–1158.

  • Prolla TA, Baker SM, Harris AC, Tsao JL, Yao X, Bronner CE, Zheng B, Gordon M, Reneker J, Arnheim N, Shibata D, Bradley A and Liskay RM . (1998). Nat. Genet., 18, 276–279.

  • Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC and Perucho M . (1997). Science, 275, 967–969.

  • Roix JJ, McQueen PG, Munson PJ, Parada LA and Misteli T . (2003). Nat.Genet., 34, 287–291.

  • Shao C, Deng L, Henegariu O, Liang L, Raikwar N, Sahota A, Stambrook PJ and Tischfield JA . (1999). Proc. Natl. Acad. Sci. USA, 96, 9230–9235.

  • Shao C, Deng L, Henegariu O, Liang L, Stambrook PJ and Tischfield JA . (2000). Proc. Natl. Acad. Sci. USA, 97, 7405–7410.

  • Shao C, Stambrook PJ and Tischfield JA . (2001). Nat. Genet., 28, 169–172.

  • Shao C, Yin M, Deng L, Stambrook PJ, Doetschman T and Tischfield JA . (2002). Oncogene, 21, 2840–2845.

  • Shin CY and Turker MS . (2002). DNA Repair (Amst), 1, 995–1001.

  • Shin CY, Mellon I and Turker MS . (2002). Oncogene, 21, 1768–1776.

  • Shoemaker AR, Haigis KM, Baker SM, Dudley S, Liskay RM and Dove WF . (2000). Oncogene, 19, 2774–2779.

  • Stambrook PJ, Shao C, Stockelman M, Boivin G, Engle SJ and Tischfield JA . (1996). Environ. Mol. Mutagen., 28, 471–482.

  • Tischfield JA and Shao C . (2003). Nat. Genet., 33, 5–6.

  • Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD and Markowitz SD . (1998). Proc. Natl. Acad. Sci. USA, 95, 8698–8702.

  • Wade CM, Kulbokas III EJ, Kirby AW, Zody MC, Mullikin JC, Lander ES, Lindblad-Toh K and Daly MJ . (2002). Nature, 420, 574–578.

  • Wijnhoven SW, Sonneveld E, Kool HJ, van Teijlingen CM and Vrieling H . (2003). Carcinogenesis, 24, 139–144.

  • Yao X, Buermeyer AB, Narayanan L, Tran D, Baker SM, Prolla TA, Glazer PM, Liskay RM and Arnheim N . (1999). Proc. Natl. Acad. Sci. USA, 96, 6850–6855.

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Acknowledgements

This work is supported by US NIH Grant R01ES011633 to JAT.

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Authors and Affiliations

  1. Department of Genetics, Rutgers University, 604 Allison Road, Piscataway, 08854-8082, NJ, USA

    Changshun Shao, Li Deng, Yanping Chen & Jay A Tischfield

  2. Departments of Genetics and Medicine, Harvard Medical School and Harvard-Partners Center for Genetics and Genomics, Boston, 02115, MA, USA

    Raju Kucherlapati

  3. Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, 45267, OH, USA

    Peter J Stambrook

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  1. Changshun Shao
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  2. Li Deng
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Correspondence to Changshun Shao or Jay A Tischfield.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Shao, C., Deng, L., Chen, Y. et al. Mlh1 mediates tissue-specific regulation of mitotic recombination. Oncogene 23, 9017–9024 (2004). https://doi.org/10.1038/sj.onc.1208148

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