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Alani, Eric
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Research
research overview
- Highly conserved mismatch repair (MMR) systems have been identified in organisms ranging from bacteria to humans that recognize and repair base pair and small insertion/deletion mismatches that arise as the result of DNA replication errors, DNA damage, and genetic recombination. In humans, mutations in MMR genes have been correlated to both an increased mutation rate and a predisposition to a hereditary form of colorectal cancer (HNPCC). HNPCC has a high cure rate if detected early, underscoring the importance of obtaining new mechanistic understandings of mismatch repair and new diagnostic tools. My current work is focused on understanding how MMR proteins identify mismatches and signal downstream factors during DNA replication and repair, and the role of genetic background in determining the penetrance of MMR mutations. 1. We are currently analyzing the behavior of single MSH and MLH complexes interacting with DNA using total internal fluorescence microscopy. These studies are aimed at distinguishing between competing models for how MSH and MLH proteins signal downstream steps in MMR. In addition, my lab is using genetic and biochemical approaches to test interactions between MMR components and the SGS1 helicase to prevent recombination between divergent DNA sequences. 2. My group is using deep sequencing technologies to examine genome-wide mutation accumulation in wild-type and MMR mutants. This work will allow us to identify mutational hotspots in yeast and humans and provide information that should help cancer researchers distinguish mutations critical for transformation to a cancer state from those that occur after transformation. 3. We are using molecular evolution approaches to study incompatibilities in MMR. This work offers new tools to identify genetic interactions in DNA repair pathways, with the overall goal of understanding the effect of genetic background on cancer susceptibility. My laboratory has been funded since 1995 by GM53085. A nice aspect of our current work is that it involves long-term collaborations with a single molecule biophysicist (Eric Greene), and a population geneticist (Charles Aquadro). The result of these efforts is a novel set of interdisciplinary approaches to study the roles of MMR in maintaining genome stability.
research activities
principal investigator on
- PREDOCTORAL TRAINING IN GENETICS & DEVELOPMENT awarded by NATL INST OF GENERAL MEDICAL SCIENCES, NIH 2007 - 2012
- PREDOCTORAL TRAINING IN GENETICS & DEVELOPMENT awarded by NATL INST OF GENERAL MEDICAL SCIENCES, NIH 2012 - 2017
- ROLES FOR MISMATCH REPAIR PROTEINS IN MAINTAINING GENOME STABILITY awarded by NATL INST OF HEALTH DHHS 2008 - 2012
- ROLES FOR MISMATCH REPAIR PROTEINS IN MAINTAINING GENOME STABILITY awarded by NATL INST OF GENERAL MEDICAL SCIENCES, NIH 2012 - 2016
area(s) of concentration/expertise
keywords
- DNA mismatch repair
- genetic incompatibility
- genetic recombination
- genome stability
- meiosis
- yeast
submitted impact statement
Publications
individual publications
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academic article
- Evolutionary rate covariation involving meiotic proteins is explained by fluctuating evolutionary pressure in yeasts and mammals. . Genetics. 193:529-38. 2013
- Genetic analysis of mlh3 mutations reveals interactions between crossover promoting factors during meiosis in baker's yeast.. G3. 3:9-22. 2013
- Evolutionary rate covariation in meiotic proteins results from fluctuating evolutionary pressure in yeasts and mammals.. Genetics. 193:529-538. 2012
- Evolutionary rate covariation reveals shared functionality, but not intermolecular coevolution, of genes.. Genome Research. 22:714-720. 2012
- Evolutionary rate covariation reveals shared functionality and co-expression of genes.. Genome Research. 22:714-720. 2012
- Multiple cellular mechanisms prevent chromosomal rearrangements involving repetitive DNA.. Critical Rev. Biochem. Mol. Biol.. 47:297-313. 2012
- Mutation hotspots in yeast caused by long-range clustering of homopolymeric sequences.. Cell Reports. 1:36-42. 2012
- Single-molecule imaging reveals target search mechanisms during DNA mismatch repair. . Proceedings of the National Academy of Sciences of the United States of America. 109. 2012
- The unstructured linker arms of Mlh1-Pms1 are important for interactions with DNA during mismatch repair. . Journal of Molecular Biology. 422:192-203. 2012
- Multiple factors insulate Msh2-Msh6 mismatch repair activity from defects in Msh2 Domain I.. Journal of Molecular Biology. 411:765-780. 2011
- Pch2 modulates chromatid partner choice during meiotic double-strand break repair in Saccharomyces cerevisiae.. Genetics. 188:511-521. 2011
- Sustained and rapid chromosome movements are critical for chromosome pairing and meiotic progression in budding yeast. . Genetics. 188:21-32. 2011
- The DNA damage checkpoint promotes recombination between divergent DNA sequences in budding yeast.. DNA Repair. 10:1086-1094. 2011
- Detection of heterozygous mutations in the genome of mismatch repair defective diploid yeast using a Bayesian approach. Genetics. 186:493-503. 2010
- Genetic analysis of baker's yeast Msh4-Msh5 reveals a threshold crossover level for meiotic viability. PLoS Genetics. 6. 2010
- The Baker's Yeast Diploid Genome is Remarkably Stable in Vegetative Growth and Meiosis. PLoS Genetics. 6. 2010
- Visualizing one-dimensional diffusion of eukaryotic DNA repair factors along a chromatin lattice.. Nature Structural and Molecular Biology. 17:932-938. 2010
- A tale of tails: Insights into the coordination of 3’ end processing during homologous recombination. BioEssays. 31:315-321. 2009
- Genomic mutation rates: What high-throughput methods can tell us.. BioEssays. 31:912-920. 2009
- The pch2del mutation in baker’s yeast alters meiotic crossover levels and confers a defect in crossover interference. . PLoS Genetics. 5. 2009
- A mutation in the putative MLH3 endonuclease domain confers a defect in both mismatch repair and meiosis in Saccharomyces cerevisiae. Genetics. 179:747-755. 2008
- Broad overexpression of ribonucleotide reductase genes in mice specifically induces lung neoplasms. . Cancer Research. 68:2652-2660. 2008
- Csm4, in collaboration with Ndj1, mediates telomere-led chromosome dynamics and recombination during yeast meiosis. . PLoS Genetics. 4. 2008
- Identification and dissection of a complex DNA repair sensitivity phenotype in baker’s yeast. PLoS Genetics. 4. 2008
- Incompatibilities involving yeast mismatch repair genes: a role for genetic modifiers and implications for disease penetrance and variation in genomic mutation rates. . PLoS Genetics. 4. 2008
- Mutants defective in Rad1-Rad10-Slx4 exhibit a unique pattern of viability during mating type switching in S. cerevisiae. . Genetics. 179:1807-1821. 2008
- Dynamic basis for one-dimensional DNA scanning by the mismatch repair complex Msh2-Msh6. Molecular Cell. 28:359-370. 2007
- Saccharomyces cerevisiae MSH2-MSH3 and MSH2-MSH6 complexes display distinct requirements for DNA binding Domain I in mismatch recognition.. Journal of Molecular Biology. 366:53-66. 2007
- The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations. Human Molecular Genetics. 16:445-452. 2007
- Accumulation of recessive lethal mutations in S. cerevisiae mlh1 mismatch repair mutants is not associated with gross chromosomal rearrangements. Genetics. 174:519-523. 2006
- Analysis of Interactions Between Mismatch Repair Initiation Factors and the Replication Processivity Factor PCNA. Journal of Molecular Biology. 355:175-184. 2006
- Mismatch Repair Factor MSH2-MSH3 Binds and Alters the Conformation of Branched DNA Structures Predicted to form During Genetic Recombination. Journal of Molecular Biology. 360:523-536. 2006
- Detection of high affinity mismatch binding and sliding clamp modes for the MSH2-MSH6 mismatch recognition complex by single-molecule unzipping force analysis. Molecular Cell. 20:771-781. 2005
- Competing crossover pathways act during meiosis in Saccharomyces cerevisiae. Genetics. 168:1805-1816. 2004
- Distinct roles for the Saccharomyces cerevisiae mismatch repair proteins in heteroduplex rejection, mismatch repair, and nonhomologous tail removal. Genetics. 169:563-574. 2004
- Heteroduplex rejection during single-strand annealing requires Sgs1 helicase and mismatch repair proteins Msh2 and msh6 but not Pms1 . Proceedings at the National Academy of Science USA. 101:9315-9320. 2004
- Mismatch Repair Proteins: Key Regulators of Genetic Recombination. Cytogenetic and Genome Research. 107:146-159. 2004
- Replication factors license Exonuclease I in mismatch repair. Molecular Cell. 15:164-166. 2004
- Crystal structure and biochemical analysis of the MutS-ADP· BeFx complex suggests a conserved mechanism for ATP interactions in mismatch repair. Journal of Biological Chemistry. 278:16088-16094. 2003
- DNA bending and unbending by MutS govern mismatch recognition and specificity. Proceedings at the National Academy of Science USA. 100:14822-14827. 2003
- Systematic mutagenesis of the Saccharomyces cerevisiae MLH1 gene reveals distinct roles for Mlh1p in meiotic crossing over and in vegetative and meiotic mismatch repair. Molecular and Cellular Biology. 23:873-886. 2003
- msh2 separation of function mutations confer defects in the initiation steps of mismatch repair. Journal of Molecular Biology. 331:123-138. 2003
- Analysis of conditional mutations in the Saccharomyces cerevisiae MLH1 gene in mismatch repair and in meiotic crossing over. Genetics. 160:909-921. 2002
- Identification of rad27 mutations that confer differential defects in mutation avoidance, repeat-tract instability, and flap cleavage. Molecular and Cellular Biology. 21:4889-4899. 2001
- MSH-MLH complexes formed at a DNA mismatch are disrupted by the PCNA sliding clamp. Journal of Molecular Biology. 306:957-968. 2001
- Analysis of yeast MSH2-MSH6 suggests that the initiation of mismatch repair can be separated into discrete steps. Journal of Molecular Biology. 302:327-338. 2000
- EXOI and MSH6 are high copy suppressors of conditional mutations in the MSH2 mismatch repair gene of S. cerevisiae. Genetics. 155:589-599. 2000
- Roles for mismatch repair factors in regulating genetic recombination. Molecular and Cellular Biology. 20:7839-7844. 2000
- The Saccharomyces cerevisiae Msh2 mismatch repair protein localizes to recombination intermediates in vivo. Molecular Cell. 5:789-799. 2000
- A mutation in the MSH6 subunit of the S. cerevisiae MSH2-MSH6 complex disrupts mismatch recognition. Journal of Biological Chemistry. 247:16115-16125. 1999
- Characterization of the microsatellite instability and mutator phenotypes conferred by a Tn3 insertion in RFC1, the large subunit of the yeast clamp loader. Genetics. 151:499-509. 1999
- Separation of function mutations in S. cerevisiae MSH2 that confer mismatch repair defects but do not affect nonhomologous tail removal during recombination. Molecular and Cellular Biology. 19:7558-7567. 1999
- The S. cerevisiae Msh2p and Msh6p ATPase activities are both required during mismatch repair. Molecular and Cellular Biology. 18:7590-7601. 1998
- Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition. Molecular and Cellular Biology. 17:2436-2447. 1997
- Saccharomyces cerevisiae MSH2, a mispaired base recognition protein, also recognizes Holliday junctions in DNA. Journal of Molecular Biology. 265:289-301. 1997
- The Saccharomyces cerevisiae Msh2p and Msh6p proteins form a complex that specifically binds to duplex oligonucleotides containing mismatched DNA base pairs. Molecular and Cellular Biology. 16:5604-5615. 1996
- The Saccharomyces cerevisiae Msh2 protein specifically binds to duplex oligonucleotides containing mismatched DNA base pairs and insertions. Genes and Development. 9:234-247. 1995
- Interaction between mismatch repair and genetic recombination in Saccharomyces cerevisiae. Genetics. 137:19-39. 1994
- Interactions between the Msh2, Mlh1 and Pms1 proteins during the initiation of DNA mismatch repair. Science. 265:1091-1093. 1994
- Mismatch repair and cancer susceptibility. Current Opinion in Biotechnology. 5:585-594. 1994
- Characterization of DNA binding and strand exchange stimulation properties of y-RPA, a yeast single strand DNA binding protein. Journal of Molecular Biology. 227:54-71. 1992
- A pathway for generation and processing of double strand breaks during meiotic recombination in S. cerevisiae. Cell. 61:1089-1101. 1990
- Analysis of wild type and rad50 mutants of yeast suggests an intimate relationship between meiotic chromosome synapsis and recombination. Cell. 61:419-436. 1990
- The yeast RAD50 gene encodes a predicted 153 kd protein containing a purine nucleotide binding domain and two large heptad repeat regions. Genetics. 122:47-57. 1989
- The RAD50 gene of S. cerevisiae. UCLA Symp.. Molecular and Cellular Biology. 83:201-215. 1988
- A method for gene disruption that allows repeated use of URA3 selection in the construction of multiply disrupted yeast strains. Genetics. 116:541-545. 1987
- A new type of fusion analysis applicable to many organisms. Protein fusions to the URA3 gene of yeast. Genetics. 117:5-12. 1987
- Analysis of the syrian hamster (Mesoerecetus auratus) reveals pronounced sexual dimorphism. Comparative Biochemistry and Physiology. 84B:403-407. 1987
- The nine amino-terminal residues of δ-aminolevulinate synthase direct β-galactosidase into the mitochondrial matrix. Molecular and Cellular Biology. 6:355-364. 1986
- Distinctly regulated upstream activation sites mediate catabolite repression of the CYC1 gene of Saccharomyces cerevisiae. Cell. 36:503-511. 1984
- Composition of the lipid droplet in embryos of the annual fish Nothobranchius guentheri. Comparative Biochemistry and Physiology. 73B:915-917. 1982
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booksection
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chapter
- DNA mismatch repair in mammals. Encyclopedia of Biological Chemistry. 2010
Teaching
teaching overview
- This section is focused on BioGD486, Eukaryotic Genetics, a four-credit course that has been my major teaching responsibility. My other teaching commitments include or have included participating in Explorations in Undergraduate Biology (Bio101-104), mentoring in undergraduate research (BioGD499), and participating, organizing, or co-organizing Graduate Topics/Problems in Genetics and Biochemistry (BioGD780, BioGD781, BioBM735), and Careers after Training in Molecular Biosciences (BioBM733). I have also served almost every year as an Adhoc thesis reviewer in the Biology Honor Program. BioGD486 was created to give undergraduate and first year graduate students training in genetic analysis that builds on fundamental concepts introduced in Introductory Genetics. Concepts in BioGD486 are presented within the context of a well-studied field, such as chromosome segregation in baker’s yeast. Genetic tools that are introduced in this context are then applied towards the study of a variety of fields such as vegetative and meiotic cell cycle control, embryonic development, and plant, population, and human genetics. My overall goal is to prepare students to independently evaluate genetic studies, to develop theories that support existing data, and to propose experimental approaches to test specific hypotheses. Students attend three hours of lecture per week, read original research papers that they then present and critically evaluate in a recitation (journal club) section, work through problem sets, and write a series of reports based on an analysis of original research articles. Students also write two in class exams and a take-home final that stress analytical approaches. Since 1997 BioGD486 has averaged 30 students per year, of which approximately 65% are undergraduates. My goal in the foreseeable future is to introduce new topics that will keep the course fresh. Each year I closely examine student evaluations and then take the necessary steps to improve my teaching skills. Since 2004 all of the course material (lectures, readings, problem sets, written assignments, old exams) are available on the web through Cornell Blackboard. A wonderful aspect of this course is that it describes a rapidly evolving field; this allows me to introduce new material and reorganize my notes on a yearly basis. Overall I am pleased with my teaching record as I feel that BioGD486 is accessible to both undergraduate and graduate students. I have been gratified to hear from undergraduate alumni who have indicated that BioGD486 provides an excellent preparation for their careers in basic research, medicine, and biotechnology.
teaching activities
Service
service to the profession
- American Society for Microbiology Member 1995 -
- Genetic Society of America Member 1995 -
- SIGMA XI Member 1984 -
- Northeast Regional Yeast Meeting Chairperson 2009
- University of Buffalo Committee Member 2008
- University of Toronto Committee Member 2008
- COLUMBIA UNIVERSITY Committee Member 2005
- Northeast Regional Yeast Meeting Chairperson 2002
reviewer or editor for
- Genetics
- NIH Genetics Study Section
- NIH Genetics Study Section
- NIH Molecular Genetics A Study Section, Challenge Grants Stage 1 Reviewer
- NIH Molecular Genetics B Study Section
- NIH Molecular Genetics B Study Section
- NIH Molecular Genetics B Study Section
- NIH Molecular Genetics B Study Section
- NIH Molecular Genetics C Study Section
- US Army Breast Cancer Research Program, MCB Study Section
- US Army Breast Cancer Research Program, MCB Study Section
Background
education and training
- Ph.D. in Biochemistry and Molecular Biology, Harvard University 1990
- B.S. in Life Sciences, Massachusetts Institute of Technology 1984
awards and honors
Other
college
- CALS
research keyword
- DNA mismatch repair
- genetic incompatibility
- genetic recombination
- genome stability
- meiosis
- yeast
name prefix
- Professor