Biological and Chemical Sciences

Prof Robert Lahue

BA, PhD.

Biography

1979 B.A. (Chemistry), University of Virginia
1984 Ph.D. (Biochemistry), University of California, Berkeley
1984-89 Postdoctoral Research Fellow, Department of Biochemistry,Duke University Medical Center. Laboratory of Dr. Paul Modrich, 2015 Nobel Laureate in Chemistry
1989-1996 Assistant Professor, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical Center
1997-2005 Associate Professor, Eppley Institute for Cancer Research, University of Nebraska Medical Center
2005-2007 Professor, Eppley Institute for Cancer Research, and Associate Director for Education and Training, UNMC Eppley Cancer Center, University of Nebraska Medical Center
2007-2011 SFI Professor of Molecular Genetics, Department of Biochemistry, NUI Galway
2011-present Professor of Molecular Genetics, School of Natural Sciences, NUI Galway

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.

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]

Peer Reviewed Journals

	Year	Publication
	(2021)	'SPYing on triplet repeat expansions: Insights into FAN1-MLH1 interaction and regulation' Robert S. Lahue (2021) 'SPYing on triplet repeat expansions: Insights into FAN1-MLH1 interaction and regulation'. Cell Reports, 36 (11) [DOI] [Details]
	(2020)	'New developments in Huntington's disease and other triplet repeat diseases: DNA repair turns to the dark side' Robert~S. Lahue (2020) 'New developments in Huntington's disease and other triplet repeat diseases: DNA repair turns to the dark side'. Neuronal Signaling, 4 (4) [DOI] [Details]
	(2020)	'Assessing Triplet Repeat Expansions in Human SVG-A Cell Culture' Williams, GM;Lahue, RS (2020) 'Assessing Triplet Repeat Expansions in Human SVG-A Cell Culture'. Methods in Molecular Biology, 2056 :151-172 [DOI] [Details]
	(2020)	'HDAC3 deacetylates the DNA mismatch repair factor MutS$\upbeta$ to stimulate triplet repeat expansions' Gregory M. Williams and Vasileios Paschalis and Janice Ortega and Frederick W. Muskett and James T. Hodgkinson and Guo-Min Li and John W. R. Schwabe and Robert S. Lahue (2020) 'HDAC3 deacetylates the DNA mismatch repair factor MutS$\upbeta$ to stimulate triplet repeat expansions'. Proceedings of the National Academy of Sciences, 117 (38):23597-23605 [DOI] [Details]
	(2017)	'A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease mice' Suelves, N,Kirkham-McCarthy, L,Lahue, RS,Gines, S (2017) 'A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease mice'. Scientific Reports, 7 [DOI] [Details]
	(2017)	'MutS beta abundance and Msh3 ATP hydrolysis activity are important drivers of CTG circle CAG repeat expansions' Keogh, N;Chan, KY;Li, GM;Lahue, RS (2017) 'MutS beta abundance and Msh3 ATP hydrolysis activity are important drivers of CTG circle CAG repeat expansions'. Nucleic Acids Research, 45 :10068-10078 [DOI] [Details]
	(2016)	'The Saccharomyces cerevisiae Mre11-Rad50-Xrs2 complex promotes trinucleotide repeat expansions independently of homologous recombination' Ye, Y; Kirkham-McCarthy L; Lahue, RS (2016) 'The Saccharomyces cerevisiae Mre11-Rad50-Xrs2 complex promotes trinucleotide repeat expansions independently of homologous recombination'. Dna Repair, 43 :1-8 [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]
	(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]
	(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]
	(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]
	(2012)	'MutS beta and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells' Gannon, AMM;Frizzell, A;Healy, E;Lahue, RS (2012) 'MutS beta and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells'. Nucleic Acids Research, 40 :10324-10333 [DOI] [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, DF;Gleeson, O;Verra, L;Schulz, D;Lahue, RS;Freudenreich, CH (2011) 'New Functions of Ctf18-RFC in Preserving Genome Stability outside Its Role in Sister Chromatid Cohesion'. Plos Genetics, 7 [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)	'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)	'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)	'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]
	(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]
	(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)	'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)	'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]
	(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]
	(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]
	(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]
	(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)	'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]
	(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]
	(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]
	(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)	'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]
	(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]
	(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]

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]
	(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. Reviews [Details]

Honours and Awards

Year	Title	Awarding Body
2015	Invited guest, Nobel Prize ceremony and banquet	Swedish Academy of Sciences
2014	Chair, 2014 Gordon Research Conference on Mutagenesis	Gordon Research Conference
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
2011	Science Foundation Ireland Principal Investigator	SFI
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