DNA Repair and Molecular Immunology

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DNA Repair and Molecular Immunology Laboratory

Barry P. Sleckman, MD, PhD, Principal Investigator

Our laboratory studies the cellular response to genomic DNA damage. Double stranded breaks (DSBs) are among the most dangerous DNA lesions as they can be resolved aberrantly forming chromosomal translocations and deletions that can lead to cellular transformation and cancer. Our main focus has been on elucidating the pathways activated by DNA DSBs generated during antigen receptor gene assembly in developing lymphocytes. More recently we have begun to study unique features of DNA DSB repair that are particularly important for cancer cells and are potential targets for novel cancer therapeutics. We are defining DSB repair pathways that function primarily to prevent un-repaired DSBs from being aberrantly resolved. We are also investigating how signals from DSBs can regulate normal cellular function by integrating with other cellular signaling pathways. To do this we use cell lines where we can induce DNA DSBs at defined genomic locations and mouse models of genome instability and cancer. In addition, we are conducting CRISPR/Cas9 screens to identify novel proteins involved in DNA DSB repair.

Active Projects

  • DNA damage repair pathways as targets for cancer therapeutics
  • Tissue-specific genetic programs activated by DNA damage
  • DNA repair pathways that repress genome instability and cancer
    • Active Grants

      • Atm Function During V(D)J Recombination
        PI: Barry Sleckman, MD, PhD
        National Institute of Allergy and Infectious Diseases (NIAID)
      • Novel DNA Double Strand Break Repair Targeting Therapeutics for Cancer Treatment
        PI: Barry Sleckman, MD, PhD
        National Cancer Institute (NCI)
      • The V(D)J Recombination Reaction and Its Impact on Lymphocyte Development
        PI: Barry Sleckman, MD, PhD
        National Institute of Allergy and Infectious Diseases (NIAID)

Body

DNA Repair and Molecular Immunology Laboratory

Barry P. Sleckman, MD, PhD, Principal Investigator

Our laboratory studies the cellular response to genomic DNA damage. Double stranded breaks (DSBs) are among the most dangerous DNA lesions as they can be resolved aberrantly forming chromosomal translocations and deletions that can lead to cellular transformation and cancer. Our main focus has been on elucidating the pathways activated by DNA DSBs generated during antigen receptor gene assembly in developing lymphocytes. More recently we have begun to study unique features of DNA DSB repair that are particularly important for cancer cells and are potential targets for novel cancer therapeutics. We are defining DSB repair pathways that function primarily to prevent un-repaired DSBs from being aberrantly resolved. We are also investigating how signals from DSBs can regulate normal cellular function by integrating with other cellular signaling pathways. To do this we use cell lines where we can induce DNA DSBs at defined genomic locations and mouse models of genome instability and cancer. In addition, we are conducting CRISPR/Cas9 screens to identify novel proteins involved in DNA DSB repair.

Active Projects

  • DNA damage repair pathways as targets for cancer therapeutics
  • Tissue-specific genetic programs activated by DNA damage
  • DNA repair pathways that repress genome instability and cancer
    • Active Grants

      • Atm Function During V(D)J Recombination
        PI: Barry Sleckman, MD, PhD
        National Institute of Allergy and Infectious Diseases (NIAID)
      • Novel DNA Double Strand Break Repair Targeting Therapeutics for Cancer Treatment
        PI: Barry Sleckman, MD, PhD
        National Cancer Institute (NCI)
      • The V(D)J Recombination Reaction and Its Impact on Lymphocyte Development
        PI: Barry Sleckman, MD, PhD
        National Institute of Allergy and Infectious Diseases (NIAID)

Selected Publications EXPAND ALL ON THIS PAGE

HCoDES reveals chromosomal DNA end structures with single-nucleotide resolution

December 18, 2014
Dorsett Y, Zhou Y, Tubbs AT, Chen BR, Purman C, Lee BS, George R, Bredemeyer AL, Zhao JY, Sodergen E, Weinstock GM, Han ND, Reyes A, Oltz EM, Dorsett D, Misulovin Z, Payton JE, Sleckman BP.

HCoDES reveals chromosomal DNA end structures with single-nucleotide resolution

Mol Cell. 2014 Dec 18;56(6):808-18.

Dorsett Y, Zhou Y, Tubbs AT, Chen BR, Purman C, Lee BS, George R, Bredemeyer AL, Zhao JY, Sodergen E, Weinstock GM, Han ND, Reyes A, Oltz EM, Dorsett D, Misulovin Z, Payton JE, Sleckman BP.

PMID: 25435138;PMCID: PMC4272619

KAP-1 promotes resection of broken DNA ends not protected by γ-H2AX and 53BP1 in G₁-phase lymphocytes

August 1, 2014
Tubbs AT, Dorsett Y, Chan E, Helmink B, Lee BS, Hung P, George R, Bredemeyer AL, Mittal A, Pappu RV, Chowdhury D, Mosammaparast N, Krangel MS, Sleckman BP.

KAP-1 promotes resection of broken DNA ends not protected by γ-H2AX and 53BP1 in G₁-phase lymphocytes

Mol Cell Biol. 2014 Aug;34(15):2811-21.

Tubbs AT, Dorsett Y, Chan E, Helmink B, Lee BS, Hung P, George R, Bredemeyer AL, Mittal A, Pappu RV, Chowdhury D, Mosammaparast N, Krangel MS, Sleckman BP.

PMID: 24842905; PMCID: PMC4135573

RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation

January 16, 2012
Bednarski JJ, Nickless A, Bhattacharya D, Amin RH, Schlissel MS, Sleckman BP.

RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation

J Exp Med. 2012 Jan 16;209(1):11-7.

Bednarski JJ, Nickless A, Bhattacharya D, Amin RH, Schlissel MS, Sleckman BP.

PMID: 22201128; PMCID: PMC3260864

The response to and repair of RAG-mediated DNA double-strand breaks

January 1, 2012
Helmink BA, Sleckman BP.

The response to and repair of RAG-mediated DNA double-strand breaks

Annu Rev Immunol. 2012;30:175-202.

Helmink BA, Sleckman BP.

PMID: 22224778; PMCID: PMC4038028

Ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases have overlapping activities during chromosomal signal joint formation

February 1, 2011
Gapud EJ, Dorsett Y, Yin B, Callen E, Bredemeyer A, Mahowald GK, Omi KQ, Walker LM, Bednarski JJ, McKinnon PJ, Bassing CH, Nussenzweig A, Sleckman BP.

Ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases have overlapping activities during chromosomal signal joint formation

Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2022-7.

Gapud EJ, Dorsett Y, Yin B, Callen E, Bredemeyer A, Mahowald GK, Omi KQ, Walker LM, Bednarski JJ, McKinnon PJ, Bassing CH, Nussenzweig A, Sleckman BP.

PMID: 21245316; PMCID: PMC3033293

H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes

January 13, 2011
Helmink BA, Tubbs AT, Dorsett Y, Bednarski JJ, Walker LM, Feng Z, Sharma GG, McKinnon PJ, Zhang J, Bassing CH, Sleckman BP.

H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes

Nature. 2011 Jan 13;469(7329):245-9.

Helmink BA, Tubbs AT, Dorsett Y, Bednarski JJ, Walker LM, Feng Z, Sharma GG, McKinnon PJ, Zhang J, Bassing CH, Sleckman BP.

PMID: 21160476; PMCID: PMC3150591

Erratum in: Nature. 2011 Apr 14;472(7342):247.

Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis

October 27, 2009
Mahowald GK, Baron JM, Mahowald MA, Kulkarni S, Bredemeyer AL, Bassing CH, Sleckman BP.

Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis

Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18339-44.

Mahowald GK, Baron JM, Mahowald MA, Kulkarni S, Bredemeyer AL, Bassing CH, Sleckman BP.

PMID: 19820166; PMCID: PMC2775277

MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks

March 16, 2009
Helmink BA, Bredemeyer AL, Lee BS, Huang CY, Sharma GG, Walker LM, Bednarski JJ, Lee WL, Pandita TK, Bassing CH, Sleckman BP.

MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks

J Exp Med. 2009 Mar 16;206(3):669-79.

Helmink BA, Bredemeyer AL, Lee BS, Huang CY, Sharma GG, Walker LM, Bednarski JJ, Lee WL, Pandita TK, Bassing CH, Sleckman BP. 

PMID: 19221393; PMCID: PMC2699138

DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes

December 11, 2008
Bredemeyer AL, Helmink BA, Innes CL, Calderon B, McGinnis LM, Mahowald GK, Gapud EJ, Walker LM, Collins JB, Weaver BK, Mandik-Nayak L, Schreiber RD, Allen PM, May MJ, Paules RS, Bassing CH, Sleckman BP.

DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes

Nature. 2008 Dec 11;456(7223):819-23.

Bredemeyer AL, Helmink BA, Innes CL, Calderon B, McGinnis LM, Mahowald GK, Gapud EJ, Walker LM, Collins JB, Weaver BK, Mandik-Nayak L, Schreiber RD, Allen PM, May MJ, Paules RS, Bassing CH, Sleckman BP.

PMID: 18849970; PMCID: PMC2605662

Dynamic regulation of c-Myc proto-oncogene expression during lymphocyte development revealed by a GFP-c-Myc knock-in mouse

February 1, 2008
Huang CY, Bredemeyer AL, Walker LM, Bassing CH, Sleckman BP.

Dynamic regulation of c-Myc proto-oncogene expression during lymphocyte development revealed by a GFP-c-Myc knock-in mouse

Eur J Immunol. 2008 Feb;38(2):342-9.

Huang CY, Bredemeyer AL, Walker LM, Bassing CH, Sleckman BP.

PMID: 18196519

Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes

June 11, 2007
Huang CY, Sharma GG, Walker LM, Bassing CH, Pandita TK, Sleckman BP.

Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes

J Exp Med. 2007 Jun 11;204(6):1371-81.

Huang CY, Sharma GG, Walker LM, Bassing CH, Pandita TK, Sleckman BP.

PMID: 17502661; PMCID: PMC2118620

Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule

June 1, 2000
Bassing CH, Alt FW, Hughes MM, D'Auteuil M, Wehrly TD, Woodman BB, Gärtner F, White JM, Davidson L, Sleckman BP.

Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule

Nature. 2000 Jun 1;405(6786):583-6.

Bassing CH, Alt FW, Hughes MM, D'Auteuil M, Wehrly TD, Woodman BB, Gärtner F, White JM, Davidson L, Sleckman BP.

PubMed PMID: 10850719.

ATM stabilizes DNA double-strand-break complexes during V(D)J recombination

Bredemeyer AL, Sharma GG, Huang CY, Helmink BA, Walker LM, Khor KC, Nuskey B, Sullivan KE, Pandita TK, Bassing CH, Sleckman BP.

ATM stabilizes DNA double-strand-break complexes during V(D)J recombination

Nature. 2006 Jul 27;442(7101):466-70.

Bredemeyer AL, Sharma GG, Huang CY, Helmink BA, Walker LM, Khor KC, Nuskey B, Sullivan KE, Pandita TK, Bassing CH, Sleckman BP.

PMID: 16799570

General Contact

Barry Sleckman, MD, PhD
Vice Chairman for Experimental Pathology
Executive Vice Chairman of Pathology and Laboratory Medicine
Weill Cornell Medical College
1300 York Avenue, F-715
New York, NY 10065
Tel: 212-746-4892
Fax: 212-746-8855
bas2022@med.cornell.edu

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