Pathology & Laboratory Medicine

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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)

Selected Publications

HCoDES reveals chromosomal DNA end structures with single-nucleotide resolution

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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.

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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

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

Barry P. Sleckman, MD, PhD

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.

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

Barry P. Sleckman, MD, PhD

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

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