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Clara L. Kielkopf, Ph.D.

Clara L. Kielkopf, Ph.D.

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About Me

Faculty Appointments

Professor - Department of Biochemistry and Biophysics (SMD)

Credentials

Post-doctoral Training & Residency

Post-doctoral Training | The Rockefeller University 2000 - 2001

Education

Ph.D. | California Institute of Technology. Biology and Chemistry. 2000

B.S. | University of Wisconsin-Madison. Molecular Biology (summa cum laude). 1994

Awards

Edward P. Evans Foundation Research Award. 2020 - 2023

Edward P. Evans Foundation Research Award. 2017 - 2019

Edward P. Evans Foundation Research Award. 2014 - 2016

Cover illustration for CSHL mRNA processing meeting abstract book. 2009

Prostate Cancer Foundation Award. 2005

March of Dimes Basil O'Connor Award. 2004

Kimmel Scholar Cancer Research Award. 2004

American Cancer Society Postdoctoral fellowship. 2000 - 2002

NSF Pre-Doctoral Fellowship. 1994 - 1997

Hilldale Fellowship, University of Wisconsin-Madison. 1993

Research

The Kielkopf lab investigates the molecular structures and interactions among key pre-mRNA splicing factors in human genetic diseases and hematologic malignancies (Trends Genetics 2017). Our recent structures of U2AF2 bound to a range of splice site signals provide a basis for understanding disease-...
The Kielkopf lab investigates the molecular structures and interactions among key pre-mRNA splicing factors in human genetic diseases and hematologic malignancies (Trends Genetics 2017). Our recent structures of U2AF2 bound to a range of splice site signals provide a basis for understanding disease-causing mutations in the splice sites of gene transcripts (PNAS 2014; Nature Commun. 2016). As a step towards viewing the architecture of multi-subunit pre-mRNA splicing factor complexes, we revealed phosphorylation-induced conformational changes in the splicing factor subunit SF1 bound to U2AF2, and demonstrated that the phosphorylated interface is essential in vivo (Structure 2013). We have further shown that recurrent, cancer-associated mutations of U2AF1 alter its RNA interactions (Leukemia 2014; PLOS Genetics 2017). Now, our immediate goal is to determine roadmaps of the key interactions among higher order 3' splice site complexes, and in future phases of the project, assist the development of therapeutics targeted at the level of pre-mRNA splicing.

We are grateful to the following organizations for research funding:

National Institutes of Health:
R01 GM070503: Molecular Recognition During pre-mRNA Splicing
R01 GM117005: Structural Control of Human Co-factors for Retroviral Gene Expression

Edward P. Evans Foundation:
Research Discovery Grant: Structural mechanisms & targeting of MDS-relevant pre-mRNA splicing factors

Publications

Journal Articles

A UHM-ULM interface with unusual structural features contributes to U2AF2 and SF3B1 association for pre-mRNA splicing.

Galardi JW, Bela VN, Jeffery N, He X, Glasser E, Loerch S, Jenkins JL, Pulvino MJ, Boutz PL, Kielkopf CL

The Journal of biological chemistry.. 2022 August 298 (8):102224. Epub 07/01/2022.

Pre-mRNA splicing factor U2AF2 recognizes distinct conformations of nucleotide variants at the center of the pre-mRNA splice site signal.

Glasser E, Maji D, Biancon G, Puthenpeedikakkal AMK, Cavender CE, Tebaldi T, Jenkins JL, Mathews DH, Halene S, Kielkopf CL

Nucleic acids research.. 2022 May 2050 (9):5299-5312. Epub 1900 01 01.

A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex.

Chatrikhi R, Feeney CF, Pulvino MJ, Alachouzos G, MacRae AJ, Falls Z, Rai S, Brennessel WW, Jenkins JL, Walter MJ, Graubert TA, Samudrala R, Jurica MS, Frontier AJ, Kielkopf CL

Cell chemical biology.. 2021 August 1928 (8):1145-1157.e6. Epub 03/08/2021.

Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing.

Maji D, Glasser E, Henderson S, Galardi J, Pulvino MJ, Jenkins JL, Kielkopf CL

The Journal of biological chemistry.. 2020 December 11295 (50):17148-17157. Epub 10/05/2020.

Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing.

Maji D, Glasser E, Henderson S, Galardi J, Pulvino MJ, Jenkins JL, Kielkopf CL

The Journal of biological chemistry.. 2020 December 11295 (50):17148-17157. Epub 1900 01 01.

A splice site-sensing conformational switch in U2AF2 is modulated by U2AF1 and its recurrent myelodysplasia-associated mutation.

Warnasooriya C, Feeney CF, Laird KM, Ermolenko DN, Kielkopf CL

Nucleic acids research.. 2020 June 448 (10):5695-5709. Epub 1900 01 01.

Cus2 enforces the first ATP-dependent step of splicing by binding to yeast SF3b1 through a UHM-ULM interaction.

Talkish J, Igel H, Hunter O, Horner SW, Jeffery NN, Leach JR, Jenkins JL, Kielkopf CL, Ares M

RNA.. 2019 August 25 (8):1020-1037. Epub 05/20/2019.

Dynamic stacking of an expected branch point adenosine in duplexes containing pseudouridine-modified or unmodified U2 snRNA sites.

Kennedy SD, Bauer WJ, Wang W, Kielkopf CL

Biochemical and biophysical research communications.. 2019 April 2511 (2):416-421. Epub 02/21/2019.

The pre-mRNA splicing and transcription factor Tat-SF1 is a functional partner of the spliceosome SF3b1 subunit via a U2AF homology motif interface.

Loerch S, Leach JR, Horner SW, Maji D, Jenkins JL, Pulvino M, Kielkopf CL

The Journal of biological chemistry.. 2019 February 22294 (8):2892-2902. Epub 12/19/2018.

Structures of SF3b1 reveal a dynamic Achilles heel of spliceosome assembly: Implications for cancer-associated abnormalities and drug discovery.

Maji D, Grossfield AM, Kielkopf CL

Biochimica et biophysica acta. Gene regulatory mechanisms.. 2019 1862 (11-12):194440. Epub 11/09/2019.

Insights from structures of cancer-relevant pre-mRNA splicing factors.

Kielkopf CL

Current opinion in genetics & development.. 2018 February 48 :57-66. Epub 11/10/2017.

Cancer-Associated Mutations Mapped on High-Resolution Structures of the U2AF2 RNA Recognition Motifs.

Glasser E, Agrawal A, Jenkins JL, Kielkopf CL

Biochemistry.. 2017 September 1256 (36):4757-4761. Epub 09/01/2017.

Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures.

Jenkins JL, Kielkopf CL

Trends in genetics : TIG.. 2017 May 33 (5):336-348. Epub 03/31/2017.

SF1 Phosphorylation Enhances Specific Binding to U2AF and Reduces Binding to 3'-Splice-Site RNA.

Chatrikhi R, Wang W, Gupta A, Loerch S, Maucuer A, Kielkopf CL

Biophysical journal.. 2016 December 20111 (12):2570-2586. Epub 1900 01 01.

Unmasking the U2AF homology motif family: a bona fide protein-protein interaction motif in disguise.

Loerch S, Kielkopf CL

RNA.. 2016 December 22 (12):1795-1807. Epub 1900 01 01.

Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival.

Fei DL, Motowski H, Chatrikhi R, Prasad S, Yu J, Gao S, Kielkopf CL, Bradley RK, Varmus H

PLoS genetics.. 2016 October 12 (10):e1006384. Epub 10/24/2016.

An extended U2AF(65)-RNA-binding domain recognizes the 3' splice site signal.

Agrawal AA, Salsi E, Chatrikhi R, Henderson S, Jenkins JL, Green MR, Ermolenko DN, Kielkopf CL

Nature communications.. 2016 March 87 :10950. Epub 03/08/2016.

Dividing and Conquering the Family of RNA Recognition Motifs: A Representative Case Based on hnRNP L.

Loerch S, Kielkopf CL

Journal of molecular biology.. 2015 September 25427 (19):2997-3000. Epub 06/20/2015.

U2AF1 mutations alter sequence specificity of pre-mRNA binding and splicing.

Okeyo-Owuor T, White BS, Chatrikhi R, Mohan DR, Kim S, Griffith M, Ding L, Ketkar-Kulkarni S, Hundal J, Laird KM, Kielkopf CL, Ley TJ, Walter MJ, Graubert TA

Leukemia.. 2015 April 29 (4):909-17. Epub 10/14/2014.

Structure-guided U2AF65 variant improves recognition and splicing of a defective pre-mRNA.

Agrawal AA, McLaughlin KJ, Jenkins JL, Kielkopf CL

Proceedings of the National Academy of Sciences of the United States of America.. 2014 December 9111 (49):17420-5. Epub 11/24/2014.

Cancer-relevant splicing factor CAPER? engages the essential splicing factor SF3b155 in a specific ternary complex.

Loerch S, Maucuer A, Manceau V, Green MR, Kielkopf CL

The Journal of biological chemistry.. 2014 June 20289 (25):17325-37. Epub 05/02/2014.

U2AF65 adapts to diverse pre-mRNA splice sites through conformational selection of specific and promiscuous RNA recognition motifs.

Jenkins JL, Agrawal AA, Gupta A, Green MR, Kielkopf CL

Nucleic acids research.. 2013 April 141 (6):3859-73. Epub 02/01/2013.

Staufen1 dimerizes through a conserved motif and a degenerate dsRNA-binding domain to promote mRNA decay.

Gleghorn ML, Gong C, Kielkopf CL, Maquat LE

Nature structural & molecular biology.. 2013 April 20 (4):515-24. Epub 03/24/2013.

Structure of phosphorylated SF1 bound to U2AF?? in an essential splicing factor complex.

Wang W, Maucuer A, Gupta A, Manceau V, Thickman KR, Bauer WJ, Kennedy SD, Wedekind JE, Green MR, Kielkopf CL

Structure.. 2013 February 521 (2):197-208. Epub 12/27/2012.

A Broad range of conformations contribute to the solution ensemble of the essential splicing factor U2AF(65).

Jenkins JL, Laird KM, Kielkopf CL

Biochemistry.. 2012 July 351 (26):5223-5. Epub 06/19/2012.

Three RNA recognition motifs participate in RNA recognition and structural organization by the pro-apoptotic factor TIA-1.

Bauer WJ, Heath J, Jenkins JL, Kielkopf CL

Journal of molecular biology.. 2012 January 27415 (4):727-40. Epub 12/02/2011.

Purification, crystallization and preliminary X-ray crystallographic analysis of a central domain of human splicing factor 1.

Gupta A, Kielkopf CL

Acta crystallographica. Section F, Structural biology and crystallization communications.. 2011 April 167 (Pt 4):486-90. Epub 03/25/2011.

Large favorable enthalpy changes drive specific RNA recognition by RNA recognition motif proteins.

McLaughlin KJ, Jenkins JL, Kielkopf CL

Biochemistry.. 2011 March 850 (9):1429-31. Epub 02/02/2011.

RNA induces conformational changes in the SF1/U2AF65 splicing factor complex.

Gupta A, Jenkins JL, Kielkopf CL

Journal of molecular biology.. 2011 February 4405 (5):1128-38. Epub 12/10/2010.

Structural basis for NADH/NAD+ redox sensing by a Rex family repressor.

McLaughlin KJ, Strain-Damerell CM, Xie K, Brekasis D, Soares AS, Paget MS, Kielkopf CL

Molecular cell.. 2010 May 2838 (4):563-75. Epub 1900 01 01.

Solution conformation and thermodynamic characteristics of RNA binding by the splicing factor U2AF65.

Jenkins JL, Shen H, Green MR, Kielkopf CL

The Journal of biological chemistry.. 2008 November 28283 (48):33641-9. Epub 10/08/2008.

Different requirements of the kinase and UHM domains of KIS for its nuclear localization and binding to splicing factors.

Manceau V, Kielkopf CL, Sobel A, Maucuer A

Journal of molecular biology.. 2008 September 5381 (3):748-62. Epub 06/17/2008.

X-ray structures of U2 snRNA-branchpoint duplexes containing conserved pseudouridines.

Lin Y, Kielkopf CL

Biochemistry.. 2008 May 2047 (20):5503-14. Epub 04/25/2008.

Structure of the central RNA recognition motif of human TIA-1 at 1.95A resolution.

Kumar AO, Swenson MC, Benning MM, Kielkopf CL

Biochemical and biophysical research communications.. 2008 March 21367 (4):813-9. Epub 01/15/2008.

Structure of a DNA repair substrate containing an alkyl interstrand cross-link at 1.65 A resolution.

Swenson MC, Paranawithana SR, Miller PS, Kielkopf CL

Biochemistry.. 2007 April 1746 (15):4545-53. Epub 03/22/2007.

Alternative conformations at the RNA-binding surface of the N-terminal U2AF(65) RNA recognition motif.

Thickman KR, Sickmier EA, Kielkopf CL

Journal of molecular biology.. 2007 February 23366 (3):703-10. Epub 12/02/2006.

Structural basis for polypyrimidine tract recognition by the essential pre-mRNA splicing factor U2AF65.

Sickmier EA, Frato KE, Shen H, Paranawithana SR, Green MR, Kielkopf CL

Molecular cell.. 2006 July 723 (1):49-59. Epub 1900 01 01.

Crystallization and preliminary X-ray analysis of a U2AF65 variant in complex with a polypyrimidine-tract analogue by use of protein engineering.

Sickmier EA, Frato KE, Kielkopf CL

Acta crystallographica. Section F, Structural biology and crystallization communications.. 2006 May 162 (Pt 5):457-9. Epub 04/12/2006.

Multiple U2AF65 binding sites within SF3b155: thermodynamic and spectroscopic characterization of protein-protein interactions among pre-mRNA splicing factors.

Thickman KR, Swenson MC, Kabogo JM, Gryczynski Z, Kielkopf CL

Journal of molecular biology.. 2006 February 24356 (3):664-83. Epub 12/07/2005.

Major phosphorylation of SF1 on adjacent Ser-Pro motifs enhances interaction with U2AF65.

Manceau V, Swenson M, Le Caer JP, Sobel A, Kielkopf CL, Maucuer A

The FEBS journal.. 2006 February 273 (3):577-87. Epub 1900 01 01.

X-ray structure of a Rex-family repressor/NADH complex insights into the mechanism of redox sensing.

Sickmier EA, Brekasis D, Paranawithana S, Bonanno JB, Paget MS, Burley SK, Kielkopf CL

Structure.. 2005 January 13 (1):43-54. Epub 1900 01 01.

U2AF homology motifs: protein recognition in the RRM world.

Kielkopf CL, Lücke S, Green MR

Genes & development.. 2004 July 118 (13):1513-26. Epub 1900 01 01.

X-ray structures of threonine aldolase complexes: structural basis of substrate recognition.

Kielkopf CL, Burley SK

Biochemistry.. 2002 October 141 (39):11711-20. Epub 1900 01 01.

A novel peptide recognition mode revealed by the X-ray structure of a core U2AF35/U2AF65 heterodimer.

Kielkopf CL, Rodionova NA, Green MR, Burley SK

Cell.. 2001 September 7106 (5):595-605. Epub 1900 01 01.

Conformational flexibility of B-DNA at 0.74 A resolution: d(CCAGTACTGG)(2).

Kielkopf CL, Ding S, Kuhn P, Rees DC

Journal of molecular biology.. 2000 February 25296 (3):787-801. Epub 1900 01 01.

Structure of a photoactive rhodium complex intercalated into DNA.

Kielkopf CL, Erkkila KE, Hudson BP, Barton JK, Rees DC

Nature structural biology.. 2000 February 7 (2):117-21. Epub 1900 01 01.

Structural effects of DNA sequence on T.A recognition by hydroxypyrrole/pyrrole pairs in the minor groove.

Kielkopf CL, Bremer RE, White S, Szewczyk JW, Turner JM, Baird EE, Dervan PB, Rees DC

Journal of molecular biology.. 2000 January 21295 (3):557-67. Epub 1900 01 01.

A structural basis for recognition of A.T and T.A base pairs in the minor groove of B-DNA.

Kielkopf CL, White S, Szewczyk JW, Turner JM, Baird EE, Dervan PB, Rees DC

Science.. 1998 October 2282 (5386):111-5. Epub 1900 01 01.

Structural basis for G.C recognition in the DNA minor groove.

Kielkopf CL, Baird EE, Dervan PB, Rees DC

Nature structural biology.. 1998 February 5 (2):104-9. Epub 1900 01 01.