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Kristin Eckert

TitleProfessor
InstitutionCollege of Medicine
DepartmentPathology
Address500 University Drive Hershey PA 17033
Mailbox: H059
Phone7175314065

 Overview 
 overview
PREFERRED TITLE/ROLE:

Professor of Pathology, and Biochemistry and Molecular Biology

GRADUATE PROGRAM AFFILIATIONS:

Biochemistry and Molecular Biology, Cell and Molecular Biology, Genetics, MD/PhD Degree Program, Integrative Biosciences

EDUCATION:

Ph.D., University of Wisconsin-Madison, 1988
Postdoctoral Training, NIH/National Institute of Environmental Health Sciences, 1988-1993

NARRATIVE:

The process of mutation is a cornerstone of Genetics. My laboratory’s research goal is to make significant scientific contributions towards the understanding of mutational processes in human cells, particularly in the context of genome evolution and disease. The process of mutagenesis represents a double-edged biological sword. On one hand, mutations are essential for life, and provide the necessary fuel driving evolution. One the other hand, uncontrolled mutations result in genome instability and disease. Our specific research niche is elucidating the role of repetitive DNA sequences in genome stability. Over 50% of the human genome is encoded by repetitive DNA elements of various types: satellite, minisatellite and microsatellite repeats. Despite their prevalence and postulated biologic functions, very little is known regarding the stability of repetitive elements in the human genome and the mechanisms of DNA replication and repair ensuring stability.

A major focus of my laboratory is on microsatellite sequences, short tandem repeats of 1-6 units per motif. Microsatellites are present on every chromosome and are highly polymorphic in human populations. Microsatellites can be important regulators of gene expression, affecting transcription rate, RNA stability, splicing efficiency, and RNA-protein interactions. Consequently, allele-length polymorphisms at common microsatellites are implicated as genetic risk factors in several diseases. The full impact of microsatellite changes on genome function has yet to be elucidated; therefore, it is of utmost importance to gain knowledge about how microsatellites arise, mutate, and eventually cease to exist at individual loci in the human genome. The goal of our interdisciplinary project, funded by the NIH, is to elucidate mechanisms defining the microsatellite life cycle in the human genome. This team project represents a collaboration integrating experimental and computational approaches. Genome-wide trends of microsatellite evolution are uncovered computationally (through analysis of sequenced primate and individual human genomes) in the Makova laboratory (PSU-UP campus), and are used to formulate hypotheses. Concomitantly, specific mechanisms are tested experimentally using the Eckert laboratory’s in vitro and ex vivo mutagenesis assays. The results of this project promise to be of considerable significance for understanding the dynamics of human genome evolution. Additionally, our research may have direct relevance to the issues of public health and clinical genetics. For example, the new information gained by our research can be used to predict the probability of each microsatellite to undergo mutation or cease to exist, and the probability of any genomic region to bear a new microsatellite. This will have major importance for assessing an individual’s disease risks, especially in the era when individual human genomes are being rapidly sequenced.

Our laboratory also is examining the role of microsatellite sequences in tumor cell genome evolution. Our working hypothesis is that the loss of biochemical pathways regulating microsatellite stability contributes to tumor genome evolution by producing phenotypic variants in key cancer-associated loci. Colorectal carcinomas (CRC) provide us with a relevant framework in which to examine our hypothesis. Microsatellite instability (MSI) is observed in numerous cancer types, but the underlying mechanistic basis is known for only a subset of tumors: those due to loss of mismatch repair (MMR). We have demonstrated that intrinsic DNA features (motif size, length, and sequence composition) contribute significantly to mutagenesis of common microsatellites, and that each motif differs with regard to mutational dynamics. In addition to MMR, our experiments have revealed that other mechanisms likely exist in human cells to ensure microsatellite stability. We hypothesize that complete and accurate human genome replication, particularly of repetitive DNA elements, requires the coordinated activities of multiple specialized DNA polymerases.

A second focus of my laboratory is replication-based mechanisms underlying structural variation at common fragile sites. Common fragile sites (CFS) are regions of the genome prone to chromosomal instability in tumor cells, but the precise DNA sequence features that characterize this fragility are not known. The most widely accepted model for chromosome breakage within CFS posits that DNA replication fork stalling precedes DNA breakage and subsequent DNA rearrangements. My laboratory has discovered that several repeated DNA elements, including microsatellites and inverted repeats, are inhibitory to replicative DNA polymerases in vitro, and that specialized DNA polymerases/ replication proteins are required to complete replication through such repeated sequences. Many microsatellite sequences have the potential for adopting non-B form DNA conformations, including Z-DNA, H-DNA (triplex) and cruciform structures. We are striving to elucidate the role that DNA secondary structure plays in human cell mutagenesis and genome evolution. We hypothesize that DNA replication inhibition within CFS is due to the density and/or arrangement of specific repetitive sequences, relative to other areas of the genome. To test this hypothesis, we are using a combination of biochemical, genetic and computational approaches. The biochemical and genetic experiments will elucidate DNA replication dynamics through CFS and the mechanisms/endogenous factors responsible for DNA breakage in human cells. Computationally, Dr. Makova’s lab is develop an algorithm to predict novel chromosomal sites at risk for instability. The identification of key cis-acting elements and trans-acting proteins may lead to understanding individual genetic risk factors and environmental exposures that act to increase chromosomal instability during neoplastic progression.


 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Guilliam TA, Jozwiakowski SK, Ehlinger A, Barnes RP, Rudd SG, Bailey LJ, Skehel JM, Eckert KA, Chazin WJ, Doherty AJ. Human PrimPol is a highly error-prone polymerase regulated by single-stranded DNA binding proteins. Nucleic Acids Res. 2015 Jan 30; 43(2):1056-68.
    View in: PubMed
  2. Ananda G, Hile SE, Breski A, Wang Y, Kelkar Y, Makova KD, Eckert KA. Microsatellite interruptions stabilize primate genomes and exist as population-specific single nucleotide polymorphisms within individual human genomes. PLoS Genet. 2014 Jul; 10(7):e1004498.
    View in: PubMed
  3. Kidane D, Chae WJ, Czochor J, Eckert KA, Glazer PM, Bothwell AL, Sweasy JB. Interplay between DNA repair and inflammation, and the link to cancer. Crit Rev Biochem Mol Biol. 2014 Mar-Apr; 49(2):116-39.
    View in: PubMed
  4. Bergoglio V, Boyer AS, Walsh E, Naim V, Legube G, Lee MY, Rey L, Rosselli F, Cazaux C, Eckert KA, Hoffmann JS. DNA synthesis by Pol ? promotes fragile site stability by preventing under-replicated DNA in mitosis. J Cell Biol. 2013 Apr 29; 201(3):395-408.
    View in: PubMed
  5. Baptiste BA, Ananda G, Strubczewski N, Lutzkanin A, Khoo SJ, Srikanth A, Kim N, Makova KD, Krasilnikova MM, Eckert KA. Mature microsatellites: mechanisms underlying dinucleotide microsatellite mutational biases in human cells. G3 (Bethesda). 2013 Mar; 3(3):451-63.
    View in: PubMed
  6. Ananda G, Walsh E, Jacob KD, Krasilnikova M, Eckert KA, Chiaromonte F, Makova KD. Distinct mutational behaviors differentiate short tandem repeats from microsatellites in the human genome. Genome Biol Evol. 2013; 5(3):606-20.
    View in: PubMed
  7. Hile SE, Shabashev S, Eckert KA. Tumor-specific microsatellite instability: do distinct mechanisms underlie the MSI-L and EMAST phenotypes? Mutat Res. 2013 Mar-Apr; 743-744:67-77.
    View in: PubMed
  8. Walsh E, Wang X, Lee MY, Eckert KA. Mechanism of replicative DNA polymerase delta pausing and a potential role for DNA polymerase kappa in common fragile site replication. J Mol Biol. 2013 Jan 23; 425(2):232-43.
    View in: PubMed
  9. Eckert KA, Sweasy JB. DNA polymerases and their role in genomic stability. Environ Mol Mutagen. 2012 Dec; 53(9):643-4.
    View in: PubMed
  10. Baptiste BA, Eckert KA. DNA polymerase kappa microsatellite synthesis: two distinct mechanisms of slippage-mediated errors. Environ Mol Mutagen. 2012 Dec; 53(9):787-96.
    View in: PubMed
  11. Wang N, Eckert KA, Zomorrodi AR, Xin P, Pan W, Shearer DA, Weisz J, Maranus CD, Clawson GA. Down-regulation of HtrA1 activates the epithelial-mesenchymal transition and ATM DNA damage response pathways. PLoS One. 2012; 7(6):e39446.
    View in: PubMed
  12. Fungtammasan A, Walsh E, Chiaromonte F, Eckert KA, Makova KD. A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? Genome Res. 2012 Jun; 22(6):993-1005.
    View in: PubMed
  13. Donigan KA, Hile SE, Eckert KA, Sweasy JB. The human gastric cancer-associated DNA polymerase ß variant D160N is a mutator that induces cellular transformation. DNA Repair (Amst). 2012 Apr 1; 11(4):381-90.
    View in: PubMed
  14. Hile SE, Wang X, Lee MY, Eckert KA. Beyond translesion synthesis: polymerase ? fidelity as a potential determinant of microsatellite stability. Nucleic Acids Res. 2012 Feb; 40(4):1636-47.
    View in: PubMed
  15. Kelkar YD, Eckert KA, Chiaromonte F, Makova KD. A matter of life or death: how microsatellites emerge in and vanish from the human genome. Genome Res. 2011 Dec; 21(12):2038-48.
    View in: PubMed
  16. Abdulovic AL, Hile SE, Kunkel TA, Eckert KA. The in vitro fidelity of yeast DNA polymerase d and polymerase e holoenzymes during dinucleotide microsatellite DNA synthesis. DNA Repair (Amst). 2011 May 5; 10(5):497-505.
    View in: PubMed
  17. Damerla RR, Knickelbein KE, Kepchia D, Jackson A, Armitage BA, Eckert KA, Opresko PL. Telomeric repeat mutagenicity in human somatic cells is modulated by repeat orientation and G-quadruplex stability. DNA Repair (Amst). 2010 Nov 10; 9(11):1119-29.
    View in: PubMed
  18. Kelkar YD, Strubczewski N, Hile SE, Chiaromonte F, Eckert KA, Makova KD. What is a microsatellite: a computational and experimental definition based upon repeat mutational behavior at A/T and GT/AC repeats. Genome Biol Evol. 2010; 2:620-35.
    View in: PubMed
  19. Prakasha Gowda AS, Polizzi JM, Eckert KA, Spratt TE. Incorporation of gemcitabine and cytarabine into DNA by DNA polymerase beta and ligase III/XRCC1. Biochemistry. 2010 Jun 15; 49(23):4833-40.
    View in: PubMed
  20. Shah SN, Hile SE, Eckert KA. Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes. Cancer Res. 2010 Jan 15; 70(2):431-5.
    View in: PubMed
  21. Shah SN, Opresko PL, Meng X, Lee MY, Eckert KA. DNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D. Nucleic Acids Res. 2010 Mar; 38(4):1149-62.
    View in: PubMed
  22. Duncan KJ, Eckert KA, Clawson GA. Mechanisms of growth inhibition in human papillomavirus positive and negative cervical cancer cells by the chloromethyl ketone protease inhibitor, succinyl-alanine-alanine-proline-phenylalanine chloromethyl ketone. J Pharmacol Exp Ther. 2009 Jul; 330(1):359-66.
    View in: PubMed
  23. Eckert KA, Hile SE. Every microsatellite is different: Intrinsic DNA features dictate mutagenesis of common microsatellites present in the human genome. Mol Carcinog. 2009 Apr; 48(4):379-88.
    View in: PubMed
  24. Shah SN, Eckert KA. Human postmeiotic segregation 2 exhibits biased repair at tetranucleotide microsatellite sequences. Cancer Res. 2009 Feb 1; 69(3):1143-9.
    View in: PubMed
  25. Lin GC, Jaeger J, Eckert KA, Sweasy JB. Loop II of DNA polymerase beta is important for discrimination during substrate binding. DNA Repair (Amst). 2009 Feb 1; 8(2):182-9.
    View in: PubMed
  26. Hile SE, Eckert KA. DNA polymerase kappa produces interrupted mutations and displays polar pausing within mononucleotide microsatellite sequences. Nucleic Acids Res. 2008 Feb; 36(2):688-96.
    View in: PubMed
  27. Jacob KD, Eckert KA. Escherichia coli DNA polymerase IV contributes to spontaneous mutagenesis at coding sequences but not microsatellite alleles. Mutat Res. 2007 Jun 1; 619(1-2):93-103.
    View in: PubMed
  28. Yu C, Gestl E, Eckert K, Allara D, Irudayaraj J. Characterization of human breast epithelial cells by confocal Raman microspectroscopy. Cancer Detect Prev. 2006; 30(6):515-22.
    View in: PubMed
  29. Sweasy JB, Lauper JM, Eckert KA. DNA polymerases and human diseases. Radiat Res. 2006 Nov; 166(5):693-714.
    View in: PubMed
  30. Dalal S, Hile S, Eckert KA, Sun KW, Starcevic D, Sweasy JB. Prostate-cancer-associated I260M variant of DNA polymerase beta is a sequence-specific mutator. Biochemistry. 2005 Dec 6; 44(48):15664-73.
    View in: PubMed
  31. Hamid S, Eckert KA. Effect of DNA polymerase beta loop variants on discrimination of O6-methyldeoxyguanosine modification present in the nucleotide versus template substrate. Biochemistry. 2005 Aug 2; 44(30):10378-87.
    View in: PubMed
  32. Gestl EE, Eckert KA. Loss of DNA minor groove interactions by exonuclease-deficient Klenow polymerase inhibits O6-methylguanine and abasic site translesion synthesis. Biochemistry. 2005 May 10; 44(18):7059-68.
    View in: PubMed
  33. Maneval ML, Eckert KA. Effects of oxidative and alkylating damage on microsatellite instability in nontumorigenic human cells. Mutat Res. 2004 Feb 26; 546(1-2):29-38.
    View in: PubMed
  34. Hile SE, Eckert KA. Positive correlation between DNA polymerase alpha-primase pausing and mutagenesis within polypyrimidine/polypurine microsatellite sequences. J Mol Biol. 2004 Jan 16; 335(3):745-59.
    View in: PubMed
  35. Meehan WJ, Samant RS, Hopper JE, Carrozza MJ, Shevde LA, Workman JL, Eckert KA, Verderame MF, Welch DR. Breast cancer metastasis suppressor 1 (BRMS1) forms complexes with retinoblastoma-binding protein 1 (RBP1) and the mSin3 histone deacetylase complex and represses transcription. J Biol Chem. 2004 Jan 9; 279(2):1562-9.
    View in: PubMed
  36. Khare V, Eckert KA. The proofreading 3'-->5' exonuclease activity of DNA polymerases: a kinetic barrier to translesion DNA synthesis. Mutat Res. 2002 Dec 29; 510(1-2):45-54.
    View in: PubMed
  37. Eckert K, Zielinski F, Lo Leggio L, Schneider E. Gene cloning, sequencing, and characterization of a family 9 endoglucanase (CelA) with an unusual pattern of activity from the thermoacidophile Alicyclobacillus acidocaldarius ATCC27009. Appl Microbiol Biotechnol. 2002 Dec; 60(4):428-36.
    View in: PubMed
  38. Eckert KA, Mowery A, Hile SE. Misalignment-mediated DNA polymerase beta mutations: comparison of microsatellite and frame-shift error rates using a forward mutation assay. Biochemistry. 2002 Aug 20; 41(33):10490-8.
    View in: PubMed
  39. Maitra M, Gudzelak A, Li SX, Matsumoto Y, Eckert KA, Jager J, Sweasy JB. Threonine 79 is a hinge residue that governs the fidelity of DNA polymerase beta by helping to position the DNA within the active site. J Biol Chem. 2002 Sep 20; 277(38):35550-60.
    View in: PubMed
  40. Eckert KA, Yan G, Hile SE. Mutation rate and specificity analysis of tetranucleotide microsatellite DNA alleles in somatic human cells. Mol Carcinog. 2002 Jul; 34(3):140-50.
    View in: PubMed
  41. Khare V, Eckert KA. The 3' --> 5' exonuclease of T4 DNA polymerase removes premutagenic alkyl mispairs and contributes to futile cycling at O6-methylguanine lesions. J Biol Chem. 2001 Jun 29; 276(26):24286-92.
    View in: PubMed
  42. Opresko PL, Shiman R, Eckert KA. Hydrophobic interactions in the hinge domain of DNA polymerase beta are important but not sufficient for maintaining fidelity of DNA synthesis. Biochemistry. 2000 Sep 19; 39(37):11399-407.
    View in: PubMed
  43. Eckert KA, Yan G. Mutational analyses of dinucleotide and tetranucleotide microsatellites in Escherichia coli: influence of sequence on expansion mutagenesis. Nucleic Acids Res. 2000 Jul 15; 28(14):2831-8.
    View in: PubMed
  44. Grünberg E, Eckert K, Karsten U, Maurer HR. Effects of differentiation inducers on cell phenotypes of cultured nontransformed and immortalized mammary epithelial cells: a comparative immunocytochemical analysis. Tumour Biol. 2000 Jul-Aug; 21(4):211-23.
    View in: PubMed
  45. Hile SE, Yan G, Eckert KA. Somatic mutation rates and specificities at TC/AG and GT/CA microsatellite sequences in nontumorigenic human lymphoblastoid cells. Cancer Res. 2000 Mar 15; 60(6):1698-703.
    View in: PubMed
  46. Eckert KA, Opresko PL. DNA polymerase mutagenic bypass and proofreading of endogenous DNA lesions. Mutat Res. 1999 Mar 8; 424(1-2):221-36.
    View in: PubMed
  47. Eckert KA, Hile SE. Alkylation-induced frameshift mutagenesis during in vitro DNA synthesis by DNA polymerases alpha and beta. Mutat Res. 1998 Dec 3; 422(2):255-69.
    View in: PubMed
  48. Grünberg E, Eckert K, Maurer HR. Prothymosin alpha1 antagonizes the inhibitory effects of transforming growth factor-beta1 on the adhesion of peripheral blood lymphocytes to human umbilical vein endothelial cells. Int J Mol Med. 1998 Apr; 1(4):741-6.
    View in: PubMed
  49. Opresko PL, Sweasy JB, Eckert KA. The mutator form of polymerase beta with amino acid substitution at tyrosine 265 in the hinge region displays an increase in both base substitution and frame shift errors. Biochemistry. 1998 Feb 24; 37(8):2111-9.
    View in: PubMed
  50. Eckert KA, Hile SE, Vargo PL. Development and use of an in vitro HSV-tk forward mutation assay to study eukaryotic DNA polymerase processing of DNA alkyl lesions. Nucleic Acids Res. 1997 Apr 1; 25(7):1450-7.
    View in: PubMed
  51. Bell JB, Eckert KA, Joyce CM, Kunkel TA. Base miscoding and strand misalignment errors by mutator Klenow polymerases with amino acid substitutions at tyrosine 766 in the O helix of the fingers subdomain. J Biol Chem. 1997 Mar 14; 272(11):7345-51.
    View in: PubMed
  52. Washington SL, Yoon MS, Chagovetz AM, Li SX, Clairmont CA, Preston BD, Eckert KA, Sweasy JB. A genetic system to identify DNA polymerase beta mutator mutants. Proc Natl Acad Sci U S A. 1997 Feb 18; 94(4):1321-6.
    View in: PubMed
  53. Hite JM, Eckert KA, Cheng KC. Factors affecting fidelity of DNA synthesis during PCR amplification of d(C-A)n.d(G-T)n microsatellite repeats. Nucleic Acids Res. 1996 Jun 15; 24(12):2429-34.
    View in: PubMed
  54. Eckert KA, Kunkel TA. Fidelity of DNA synthesis catalyzed by human DNA polymerase alpha and HIV-1 reverse transcriptase: effect of reaction pH. Nucleic Acids Res. 1993 Nov 11; 21(22):5212-20.
    View in: PubMed
  55. Eckert KA, Kunkel TA. Effect of reaction pH on the fidelity and processivity of exonuclease-deficient Klenow polymerase. J Biol Chem. 1993 Jun 25; 268(18):13462-71.
    View in: PubMed
  56. Lacey SF, Reardon JE, Furfine ES, Kunkel TA, Bebenek K, Eckert KA, Kemp SD, Larder BA. Biochemical studies on the reverse transcriptase and RNase H activities from human immunodeficiency virus strains resistant to 3'-azido-3'-deoxythymidine. J Biol Chem. 1992 Aug 5; 267(22):15789-94.
    View in: PubMed
  57. Eckert KA, Kunkel TA. DNA polymerase fidelity and the polymerase chain reaction. PCR Methods Appl. 1991 Aug; 1(1):17-24.
    View in: PubMed
  58. Eckert KA, Kunkel TA. High fidelity DNA synthesis by the Thermus aquaticus DNA polymerase. Nucleic Acids Res. 1990 Jul 11; 18(13):3739-44.
    View in: PubMed
  59. Eckert KA, Ingle CA, Drinkwater NR. N-ethyl-N-nitrosourea induces A:T to C:G transversion mutations as well as transition mutations in SOS-induced Escherichia coli. Carcinogenesis. 1989 Dec; 10(12):2261-7.
    View in: PubMed
  60. Eckert KA, Ingle CA, Klinedinst DK, Drinkwater NR. Molecular analysis of mutations induced in human cells by N-ethyl-N-nitrosourea. Mol Carcinog. 1988; 1(1):50-6.
    View in: PubMed
  61. Eckert KA, Drinkwater NR. recA-dependent and recA-independent N-ethyl-N-nitrosourea mutagenesis at a plasmid-encoded herpes simplex virus thymidine kinase gene in Escherichia coli. Mutat Res. 1987 May; 178(1):1-10.
    View in: PubMed
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