Robert Lahue

Personal Professor BA, PhD.

Contact Details

Personal Professor
Biochemistry
NUI Galway

T: Ext. 5756
E: bob.lahue@nuigalway.ie
 
researcher

Biography

Our chromosomes constantly undergo the opposing forces of DNA mutagenesis and DNA repair. The balance between these two forces determines the genetic fate of our cells. Normally, DNA repair wins and our genome is kept healthy. If DNA repair fails, mutagenesis ensues, often with detrimental health effects.

One enigmatic exception is DNA containing trinucleotide repeats. Mutagenesis is incredibly frequent at trinucleotide repeats in families with certain hereditary neurological diseases. These site-specific expansions, or gains of triplet repeats, occur in cells that appear otherwise normal.

These features suggest that the usual rules governing mutagenesis and repair no longer apply, and that protein activities are altered when acting at triplet repeats.

We use the budding yeast Saccharomyces cerevisiae and tissue culture cells derived from human brain (fig 1) to study the genetic mechanisms of mutagenesis and repair at trinucleotide repeats.

We continue to identify yeast proteins that either inhibit or promote triplet repeat expansions, using genetic and biochemical approaches.

Once known, we look at human homologs of these yeast proteins to see if they function analogously in cultured cells of the human CNS.

Research Interests

DNA Repair and Mutagenesis in Human Neurological Disease

Our chromosomes constantly undergo the opposing forces of DNA mutagenesis and DNA repair. The balance between these two forces determines the genetic fate of our cells. Normally, DNA repair wins and our genome is kept healthy. If DNA repair fails, mutagenesis ensues, often with detrimental health effects.

One enigmatic exception is DNA containing trinucleotide repeats. Mutagenesis is incredibly frequent at trinucleotide repeats in families with certain hereditary neurological diseases. These site-specific expansions, or gains of triplet repeats, occur in cells that appear otherwise normal.

These features suggest that the usual rules governing mutagenesis and repair no longer apply, and that protein activities are altered when acting at triplet repeats.

We use the budding yeast Saccharomyces cerevisiae and tissue culture cells derived from human brain (fig 1) to study the genetic mechanisms of mutagenesis and repair at trinucleotide repeats.

We continue to identify yeast proteins that either inhibit or promote triplet repeat expansions, using genetic and biochemical approaches.

Once known, we look at human homologs of these yeast proteins to see if they function analogously in cultured cells of the human CNS.

Peer Reviewed Journals

  Year Publication
(2014) 'RTEL1 Inhibits Trinucleotide Repeat Expansions and Fragility'
Frizzell, A,Nguyen, JHG,Petalcorin, MIR,Turner, KD,Boulton, SJ,Freudenreich, CH,Lahue, RS (2014) 'RTEL1 Inhibits Trinucleotide Repeat Expansions and Fragility'. Cell Reports, 6 :827-835 [DOI] [Details]
(2014) 'Nucleotide excision repair and the 26S proteasome function together to promote trinucleotide repeat expansions'
Concannon, C,Lahue, RS (2014) 'Nucleotide excision repair and the 26S proteasome function together to promote trinucleotide repeat expansions'. Dna Repair, 13 :42-49 [DOI] [Details]
(2013) 'Trinucleotide repeat expansions catalyzed by human cell-free extracts'
Stevens, JR,Lahue, EE,Li, GM,Lahue, RS (2013) 'Trinucleotide repeat expansions catalyzed by human cell-free extracts'. Cell Research, 23 :565-572 [DOI] [Details]
(2013) 'The 26S proteasome drives trinucleotide repeat expansions'
Concannon, C,Lahue, RS (2013) 'The 26S proteasome drives trinucleotide repeat expansions'. Nucleic Acids Research, 41 :6098-6108 [DOI] [Details]
(2012) 'MutSβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells'
Anne-Marie M. Gannon, Aisling Frizzell, Evan Healy, and Robert S. Lahue (2012) 'MutSβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells'. Nucleic Acids Research, 40 :10324-10333 [Details]
(2012) 'Histone deacetylase complexes as caretakers of genome stability'
Lahue, RS,Frizzell, A (2012) 'Histone deacetylase complexes as caretakers of genome stability'. Epigenetics, 7 :806-810 [DOI] [Details]
(2012) 'Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions'
Debacker, K,Frizzell, A,Gleeson, O,Kirkham-McCarthy, L,Mertz, T,Lahue, RS (2012) 'Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions'. Plos Biology, 10 [DOI] [Details]
(2011) 'New functions of Ctf18-RFC in preserving genome stability outside its role in sister chromatid cohesion'
Gellon, L., Razidlo, D. F., Gleeson, O., Verra, L., Schulz, D, Lahue, R. S., and Freudenreich, C. H. (2011) 'New functions of Ctf18-RFC in preserving genome stability outside its role in sister chromatid cohesion'. Plos Genetics, 7 [DOI] [Details]
(2008) 'Rapid unwinding of triplet repeat hairpins by Srs2 helicase of Saccharomyces cerevisiae'
Dhar, A,Lahue, RS (2008) 'Rapid unwinding of triplet repeat hairpins by Srs2 helicase of Saccharomyces cerevisiae'. Nucleic Acids Research, 36 :3366-3373 [DOI] [Details]
(2008) 'Mrc1, Tof1 and Csm3 inhibit CAG.CTG repeat instability by at least two mechanisms'
Razidlo, DF,Lahue, RS (2008) 'Mrc1, Tof1 and Csm3 inhibit CAG.CTG repeat instability by at least two mechanisms'. Dna Repair, 7 :633-640 [DOI] [Details]
(2008) 'Partial reconstitution of DNA large loop repair with purified proteins from Saccharomyces cerevisiae'
Sommer, D,Stith, CM,Burgers, PMJ,Lahue, RS (2008) 'Partial reconstitution of DNA large loop repair with purified proteins from Saccharomyces cerevisiae'. Nucleic Acids Research, 36 :4699-4707 [DOI] [Details]
(2008) 'Anc1, a protein associated with multiple transcription complexes, is involved in postreplication repair pathway in S. cerevisiae'
Erlich, R. L., Fry, R. C., Begley, T. J., Daee, D. L., Lahue, R. S., Samson, L. D. (2008) 'Anc1, a protein associated with multiple transcription complexes, is involved in postreplication repair pathway in S. cerevisiae'. PLoS ONE, 3 (e3717) [Details]
(2007) 'Expansions of CAG.CTG repeats in immortalized human astrocytes'
Claassen, DA,Lahue, RS (2007) 'Expansions of CAG.CTG repeats in immortalized human astrocytes'. Human Molecular Genetics, 16 :3088-3096 [DOI] [Details]
(2007) 'Post-replication repair inhibits CAGoCTG repeat expansions in Saccharomyces cerevisiae'
Daee, D.L., Mertz, T. and Lahue, R. S. (2007) 'Post-replication repair inhibits CAGoCTG repeat expansions in Saccharomyces cerevisiae'. Molecular and Cellular Biology, 27 :102-110 [Details]
(2007) 'Rev1 enhances CAGoCTG repeat stability in Saccharomyces cerevisiae'
Collins, N.S, Bhattacharyya, S. and Lahue, R. S. (2007) 'Rev1 enhances CAGoCTG repeat stability in Saccharomyces cerevisiae'. DNA Repair, 6 :38-44 [Details]
(2006) 'CAGoCTG repeat instability in cultured human astrocytes'
Farrell, B.T. and Lahue, R.S. (2006) 'CAGoCTG repeat instability in cultured human astrocytes'. Nucleic Acids Res, 34 :4495-4505 [Details]
(2005) 'Mechanistic features of CAGoCTG repeat contractions in cultured cells revealed by a novel genetic assay'
Pelletier, R., Farrell, B. T., Miret, J. J., and Lahue, R. S. (2005) 'Mechanistic features of CAGoCTG repeat contractions in cultured cells revealed by a novel genetic assay'. Nucleic Acids Res, 33 :5667-5676 [Details]
(2005) 'Srs2 helicase of Saccharomyces cerevisiae selectively unwinds triplet repeat DNA'
Bhattacharyya, S. and Lahue, R. S. (2005) 'Srs2 helicase of Saccharomyces cerevisiae selectively unwinds triplet repeat DNA'. J. Biol. Chem, 280 :33311-33317 [Details]
(2004) 'DNA elements important for CAGoCTG repeat thresholds in Saccharomyces cerevisiae'
Dixon, M. J. and Lahue, R. S. (2004) 'DNA elements important for CAGoCTG repeat thresholds in Saccharomyces cerevisiae'. Nucleic Acids Res, 32 :1289-1297 [Details]
(2004) 'Yeast Srs2 DNA helicase selectively blocks expansions of trinucleotide repeats'
Bhattacharyya, S. and Lahue, R. S. (2004) 'Yeast Srs2 DNA helicase selectively blocks expansions of trinucleotide repeats'. Mol. Cell. Biol, 24 :7324-7330 [Details]
(2004) 'DNA Polymerase ?, RFC, and PCNA are required for repair synthesis of large looped heteroduplexes in Saccharomyces cerevisiae'
Corrette-Bennett, S. E., Borgeson, C., Sommer, D., Burgers, P. M. J., and Lahue, R. S. (2004) 'DNA Polymerase ?, RFC, and PCNA are required for repair synthesis of large looped heteroduplexes in Saccharomyces cerevisiae'. Nucleic Acids Res, 32 :6268-6275 [Details]
(2003) 'DNA repair and trinucleotide repeat instability'
Lahue, R. S. and Slater, D. L. (2003) 'DNA repair and trinucleotide repeat instability'. Frontiers In Bioscience, 8 :s553-565 [Details]
(2003) 'Replication and expansion of trinucleotide repeats in yeast'
Pelletier, R., Krasilnikova, M. M., Samadashwily, G. M., Lahue, R., and Mirkin, S. M. (2003) 'Replication and expansion of trinucleotide repeats in yeast'. Mol. Cell. Biol, 23 :1349-1357 [Details]
(2002) 'Examining the potential role of DNA polymerases eta and zeta in triplet repeat instability in yeast'
Dixon, M. J. and Lahue, R. S. (2002) 'Examining the potential role of DNA polymerases eta and zeta in triplet repeat instability in yeast'. DNA Repair, 1 :765-773 [Details]
(2002) 'Identification of RTG2 as a modifier gene for CTGoCAG repeat instability in Saccharomyces cerevisiae'
Bhattacharyya, S., Rolfsmeier, M. L., Dixon, M. J., Wagoner, K. and Lahue, R. S. (2002) 'Identification of RTG2 as a modifier gene for CTGoCAG repeat instability in Saccharomyces cerevisiae'. Genetics, 162 :579-589 [Details]
(2001) 'Efficient repair of large DNA loops in Saccharomyces cerevisiae'
Corrette-Bennett, S. E., Mohlman, N. L., Rosado, Z., Miret, J. J., Hess, P. M., Parker, B. O., and Lahue, R. S. (2001) 'Efficient repair of large DNA loops in Saccharomyces cerevisiae'. Nucleic Acids Research, 29 :4143-4143 [Details]
(2001) 'Cis-elements regulating trinucleotide repeat instability in Saccharomyces cerevisiae'
Rolfsmeier, M. L., Dixon, M. J., Pessoa-Brandao, L., Pelletier, R., Miret, J. J. and Lahue, R. S. (2001) 'Cis-elements regulating trinucleotide repeat instability in Saccharomyces cerevisiae'. Genetics, 157 :1569-1579 [Details]
(2000) 'Mismatch repair blocks expansions of interrupted trinucleotide repeats in yeast'
Rolfsmeier, M. L., Dixon, M. J., and Lahue, R. S. (2000) 'Mismatch repair blocks expansions of interrupted trinucleotide repeats in yeast'. Molec. Cell, 6 :1501-1507 [Details]
(2000) 'Stabilizing effects of interruptions on trinucleotide repeat expansions in Saccharomyces cerevisiae'
Rolfsmeier, M. L., and Lahue, R. S. (2000) 'Stabilizing effects of interruptions on trinucleotide repeat expansions in Saccharomyces cerevisiae'. Mol. Cell. Biol, 20 :173-180 [Details]
(1999) 'Correction of large mispaired DNA loops by extracts of Saccharomyces cerevisiae'
Corrette-Bennett, S. E., Parker, B. O., Mohlman, N. L., and Lahue, R. S. (1999) 'Correction of large mispaired DNA loops by extracts of Saccharomyces cerevisiae'. J. Biol. Chem, 274 :17605-17611 [Details]
(1999) 'Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats'
Spiro, C., Pelletier, R., Rolfsmeier, M. L., Dixon, M. J., Lahue, R. S., Gupta, G., Park, M. S., Chen, X., Mariappan, S. V. S., and McMurray, C. T. (1999) 'Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats'. Molec. Cell, 4 :1079-1085 [Details]
(1998) 'Orientation-dependent and sequence-specific expansions of CTG/CAG trinucleotide repeats in Saccharomyces cerevisiae'
Miret, J. J., Pessoa-Brandao, L., and Lahue, R. S. (1998) 'Orientation-dependent and sequence-specific expansions of CTG/CAG trinucleotide repeats in Saccharomyces cerevisiae'. Proc. Natl. Acad. Sci, 95 :12438-12443 [Details]
(1997) 'Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition'
Alani, E., Sokolsky, T., Studamire, B., Miret, J. J. and Lahue, R S. (1997) 'Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition'. Mol. Cell. Biol, :2436-2447 [Details]
(1997) 'Instability of CAG and CTG trinucleotide repeats in Saccharomyces cerevisiae'
Miret, J. J., Pessoa-Brandao, L., and Lahue, R. S. (1997) 'Instability of CAG and CTG trinucleotide repeats in Saccharomyces cerevisiae'. Molecular And Cellular Biology, 17 :3382-3387 [Details]
(1997) 'Differential effects of the mismatch repair genes MSH2 and MSH3 on homeologous recombination in Saccharomyces cerevisiae'
Selva, E. M., Maderazo, A. B., and Lahue, R. S. (1997) 'Differential effects of the mismatch repair genes MSH2 and MSH3 on homeologous recombination in Saccharomyces cerevisiae'. Molecular And General Genetics, [Details]
(1996) 'Recognition of DNA insertion/deletion mismatches by an activity in S. Cerevisiae'
Miret, J. J., Parker, B. O. and Lahue, R. S. (1996) 'Recognition of DNA insertion/deletion mismatches by an activity in S. Cerevisiae'. Nucleic Acids Research, 24 :721-729 [Details]
(1995) 'Mismatch correction acts as a barrier to homeologous recombination in Saccharomyces cerevisiae'
Selva, E. M., New, L., Crouse, G. F., and Lahue, R. S. (1995) 'Mismatch correction acts as a barrier to homeologous recombination in Saccharomyces cerevisiae'. Genetics, 139 :1175-1188 [Details]
(1993) 'Characterization of a DNA mismatch binding activity from yeast'
Miret, J. J., Milla, M., and Lahue, R. S. (1993) 'Characterization of a DNA mismatch binding activity from yeast'. J. Biol. Chem, 268 :3507-3513 [Details]
(1993) 'Methyl-directed mismatch repair is bidirectional'
Cooper, D. L., Lahue, R. S., and Modrich, P. (1993) 'Methyl-directed mismatch repair is bidirectional'. J. Biol. Chem, 268 :11823-11829 [Details]
(1989) 'DNA mismatch correction in a defined system'
Lahue, R. S., Au, K. G., and Modrich, P. (1989) 'DNA mismatch correction in a defined system'. Science, 245 :160-164 [Details]
(1988) 'Mispair specificity of methyl-directed mismatch correction in vitro'
Su, S-S., Lahue, R. S., Au, K. G., and Modrich, P. (1988) 'Mispair specificity of methyl-directed mismatch correction in vitro'. J. Biol. Chem, 263 :6829-6835 [Details]
(1988) 'Methyl-directed mismatch correction in vitro'
Lahue, R. S., and Modrich, P. (1988) 'Methyl-directed mismatch correction in vitro'. Mutation Research, 207 :37-43 [Details]
(1987) 'Analysis of methyl-directed mismatch repair in vitro'
Lahue, R. S., Su, S-s., Welsh, K. W., and Modrich, P. (1987) 'Analysis of methyl-directed mismatch repair in vitro'. UCLA Symp. Mol. Cell. Biol, :125-134 [Details]
(1987) 'Requirement for d GATC sequences in Escherichia coli mutHLS mismatch correction'
Lahue, R. S., Su, S-s., and Modrich, P. (1987) 'Requirement for d GATC sequences in Escherichia coli mutHLS mismatch correction'. Proc. Natl. Acad. Sci, 84 :1482-1486 [Details]
(1986) 'Communication between polypeptide chains in aspartate transcarbamoylase: conformational changes at the active sites of unliganded chains resulting from ligand binding to other chains'
Lahue, R. S., and Schachman, H. K. (1986) 'Communication between polypeptide chains in aspartate transcarbamoylase: conformational changes at the active sites of unliganded chains resulting from ligand binding to other chains'. J. Biol. Chem, 261 :3079-3084 [Details]
(1984) 'The influence of quaternary structure on the active site of an oligomeric enzyme, catalytic subunit of aspartate transcarbamoylase'
Lahue, R. S., and Schachman, H. K. (1984) 'The influence of quaternary structure on the active site of an oligomeric enzyme, catalytic subunit of aspartate transcarbamoylase'. J. Biol. Chem, 259 :13906-13913 [Details]
(1980) 'Terbium luminescence as a probe of the calcium binding site of trypsin and ?-chymostrypsin'
DeJersey, J. D., Lahue, R. S., and Martin, R. B. (1980) 'Terbium luminescence as a probe of the calcium binding site of trypsin and ?-chymostrypsin'. Arch. Biochem. Biophys, 205 :536-542 [Details]

Other Journals

  Year Publication
(1996) 'Mismatch repair in replication fidelity, genetic recombination and cancer biology'
Modrich, P., and Lahue, R. S. (1996) 'Mismatch repair in replication fidelity, genetic recombination and cancer biology' Annu. Rev. Biochemistry, 65 :101-133. [Details]

Other Item

  Year Publication
(2004) Genetic asays for triplet repeat instability in yeast. Methods Mol. Biol.
Bhattacharyya, S, Dixon, MD, and Lahue, RS (2004) Genetic asays for triplet repeat instability in yeast. Methods Mol. Biol. Other Item [Details]

Reviews

  Year Publication
(2004) DNA mismatch repair and trinucleotide repeat instability: the expansion connection. ChemTracts-Biochemistry and Molecular Biology.
Lahue, RS (2004) DNA mismatch repair and trinucleotide repeat instability: the expansion connection. ChemTracts-Biochemistry and Molecular Biology. Reviews [Details]
(2003) DNA repair and trinucleotide repeat instability. Frontiers in Bioscience.
Lahue, RS and Slater, DL (2003) DNA repair and trinucleotide repeat instability. Frontiers in Bioscience. Reviews [Details]

Honours and Awards

  Year Title Awarding Body
2011 Science Foundation Ireland Principal Investigator SFI
2013 Winner, Irish Laboratory Awards "Medical Laboratory of the Year" and "Pharmaceutical Laboratory of the Year" The Irish Laboratory Awards
2013 Editorial Board Member, DNA Repair DNA Repair
2014 Chair, 2014 Gordon Research Conference on Mutagenesis Gordon Research Conference
2010 Elected Vice-Chair, 2012 Gordon Research Conference, “Mutagenesis” Gordon Research Conference
2009 Editorial Board Member, Journal of Molecular Cell Biology Journal of Molecular Cell Biology
2007 Science Foundation Ireland funded Principal Investigator Science Foundation Ireland
2006 Chair, NIH Molecular Genetics C Study Section NIH
2004 Outstanding teaching award, University of Nebraska Medical Center University of Nebraska Medical Center
2001 Tenure awarded, University of Nebraska Medical Center University of Nebraska Medical Center
1991 American Cancer Society Junior Faculty Research Award American Cancer Society
1988 NIH Postdoctoral Fellow, Duke University Medical Center NIH
1985 Damon Runyon-Walter Winchell Postdoctoral Fellow, Duke University Medical Center Damon Runyon-Walter Winchell Cancer Research Fund
1979 Regents Fellow, University of California University of California, Berkeley
1979 Phi Beta Kappa, summa cum laude, Alpha Chi Sigma Award in Chemistry, University of Virginia University of Virginia