Keck School Faculty

Michael R. Lieber, MD, PhD
Michael R. Lieber, MD, PhD
Professor of Pathology;Rita and Edward Polusky Chair in Basic Cancer Research
Pathology
NTT 1441 Eastlake Ave Health Sciences Campus Los Angeles
The web page for the Lieber lab is: lieber.usc.edu

The following overview of research at the Lieber lab is taken from lieber.usc.edu.

DNA double-strand breaks occur as part of the physiologic development of the immune repertoire in B and T lymphocytes. We study the manner in which these breaks are generated in a process called V(D)J recombination. Defects in the normal enzymes that generate these breaks can result in inherited forms of human severe combined immune deficiency (SCID). We study the biochemistry of how these proteins function, and we study how mutations in them result in SCID. Once DNA breaks are generated, they must be repaired. All cells of the body possess the ability to repair double-strand DNA breaks because all cells must deal with pathologic breaks in DNA that arise due to external radiation or due to free radicals of oxidative metabolism. The major pathway for repairing double-strand breaks in mammalian cells is called nonhomologous DNA end joining (NHEJ). If this pathway is defective in lymphocytes, then the breaks generated can not be repaired. Such defects also result in SCID. If the NHEJ pathway is defectve in all cells of the body, not only is the immune system affected, but the entire body is extremely vulnerable to ionizing radiation. Our laboratory has made substantial progress in defining proteins important in the NHEJ pathway. The first protein in the NHEJ pathway, Ku, binds at the broken DNA ends. The Artemis:DNA-PKcs complex is recruited to the DNA end by Ku. This binding activates the protein kinase activity of DNA-PKcs, which then phosphorylates Artemis and makes the Artemis:DNA-PKcs complex a potent nuclease for trimming DNA ends. Polymerase mu and lambda fill-in gaps, and polymerase mu can add nucleotides template-indepenently, like TdT. Finally, DNA ligase IV, XRCC4, and XLF form the ligation complex which ligates the double-strand break. We are interested in how all of these proteins carry out their functions and how their structure is important for this, and we are interested in identifying any other proteins that might be in th is pathway. We are also interested in how chromatin structure affects these proteins as they repair DNA breaks. The process of NHEJ is intrinsically imprecise. We suspect that this imprecision may contribute to the aging of somatic cells over time as well as to cancer. We are currently investigating this possibility using cell culture models, animal models, and analysis of human cells. Identification of inhibitors of NHEJ would be useful in cancer therapy and in improving gene targeting in human stem cells, and hence, we are trying to identify inhibitors of the pathway and individual components.

Mistakes of V(D)J recombination account for about 40% of nonHodgkin's lymphoma. We study how the normal V(D)J recombination process goes awry. Specifically, why do some ends fail to join properly, and why do some sites adjacent to oncogenes get cleaved inadvertently. The inadvertent cleavage of some sites may be due to an altered DNA structure at those sites. We are trying to understand the extent to which such DNA structural deviations contribute to the fragility of such common chromosomal translocation hotspots.

Class switch recombination is a second developmentally programmed gene rearrangement process in the vertebrate immune system, and it occurs in B cells at the Ig heavy chain locus. Class switching is the process that results in IgM being converted to IgG, IgA, or IgE. Humans borne with defects in class switching die early in life because they can not make IgA for protection of their lungs. The enzyme that initiates the class switch gene rearrangement process is a cytidine deaminase, called AID, that only functions on single-stranded DNA. We have focused on how the class switch recombination regions become single-stranded. Upon transcription, the RNA remains associated with the template DNA strand, resulting in an R-loop structure. The R-loop structure provides a substantial amount of single-stranded DNA at which the AID enzyme can act. We are interested in determining the factors that favor R-loop formation. In some lymphomas, the class switch recombination process goes awry, just as in V(D)J recombination. We are also studying these events.

In summary, the Lieber lab focuses on how physiologic and pathologic gene rearrangements function in the immune system and in cancer and aging.

Reply: Radiation Dose Does Matter: Mechanistic Insights into DNA Damage and Repair Support the Linear No-Threshold Model of Low-Dose Radiation Health Risks J Nucl Med. 2019 Jan 10. . View in PubMed

Reply: Radiation Dose Does Matter: Mechanistic Insights into DNA Damage and Repair Support the Linear No-Threshold Model of Low- Dose Radiation Health Risks J Nucl Med. 2018 Sep 27. . View in PubMed

Radiation Dose Does Matter: Mechanistic Insights into DNA Damage and Repair Support the Linear No-Threshold Model of Low-Dose Radiation Health Risks J Nucl Med. 2018 Jul; 59(7):1014-1016. . View in PubMed

Radiation Dose Does Matter: Mechanistic Insights into DNA Damage and Repair Support the Linear No-Threshold Model of Low-Dose Radiation Health Risks J Nucl Med. 2018 May 31. . View in PubMed

Concept of DNA Lesion Longevity and Chromosomal Translocations Trends Biochem Sci. 2018 May 04. . View in PubMed

DNA Repair After Exposure to Ionizing Radiation Is Not Error-Free J Nucl Med. 2018 Feb; 59(2):348. . View in PubMed

Reply: Radiation Dose Does Matter: Mechanistic Insights into DNA Damage and Repair Support the Linear No-Threshold Model of Low-Dose Radiation Health Risks J Nucl Med 2018 11; 59(11):1780-1781. . View in PubMed

Concept of DNA Lesion Longevity and Chromosomal Translocations Trends Biochem Sci. 2018 07; 43(7):490-498. . View in PubMed

Nonhomologous DNA end-joining for repair of DNA double-strand breaks J Biol Chem. 2018 07 06; 293(27):10512-10523. . View in PubMed

Nonhomologous DNA End Joining for Repair of DNA Double-Strand Breaks J Biol Chem. 2017 Dec 14. . View in PubMed

AID and Reactive Oxygen Species Can Induce DNA Breaks within Human Chromosomal Translocation Fragile ZonesMol Cell. 2017 Dec 07; 68(5):901-912. e3. . View in PubMed

DNA Ligase IV Guides End-Processing Choice during Nonhomologous End Joining Cell Rep. 2017 Sep 19; 20(12):2810-2819. . View in PubMed

Bridging of double-stranded breaks by the nonhomologous end-joining ligation complex is modulated by DNA end chemistry Nucleic Acids Res. 2017 Feb 28; 45(4):1872-1878. . View in PubMed

Non-homologous DNA end joining and alternative pathways to double-strand break repair Nat Rev Mol Cell Biol. 2017 08; 18(8):495-506. . View in PubMed

Effects of DNA end configuration on XRCC4-DNA ligase IV and its stimulation of Artemis activity J Biol Chem. 2017 08 25; 292(34):13914-13924. . View in PubMed

Bridging of double-stranded breaks by the nonhomologous end-joining ligation complex is modulated by DNA end chemistry Nucleic Acids Res. 2017 02 28; 45(4):1872-1878. . View in PubMed

Different DNA End Configurations Dictate Which NHEJ Components Are Most Important for Joining Efficiency J Biol Chem. 2016 Nov 18; 291(47):24377-24389. . View in PubMed

Dissecting the Roles of Divergent and Convergent Transcription in Chromosome Instability Cell Rep. 2016 Feb 09; 14(5):1025-1031. . View in PubMed

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci Cancer Epidemiol Biomarkers Prev. 2016 12; 25(12):1609-1618. . View in PubMed

SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV DNA Repair (Amst). 2016 07; 43:18-23. . View in PubMed

RNA Polymerase Collision versus DNA Structural Distortion: Twists and Turns Can Cause Break Failure Mol Cell. 2016 05 05; 62(3):327-334. . View in PubMed

Real-time analysis of RAG complex activity in V(D)J recombination Proc Natl Acad Sci U S A. 2016 10 18; 113(42):11853-11858. . View in PubMed

Mechanisms of human lymphoid chromosomal translocations Nat Rev Cancer. 2016 05 25; 16(6):387-98. . View in PubMed

Convergent BCL6 and lncRNA promoters demarcate the major breakpoint region for BCL6 translocations Blood. 2015 Oct 01; 126(14):1730-1. . View in PubMed

Effect of CpG dinucleotides within IgH switch region repeats on immunoglobulin class switch recombination Mol Immunol. 2015 Aug; 66(2):284-9. . View in PubMed

Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia Nat Immunol. 2015 Jul; 16(7):766-774. . View in PubMed

Organization and dynamics of the nonhomologous end-joining machinery during DNA double-strand break repair Proc Natl Acad Sci U S A. 2015 May 19; 112(20):E2575-84. . View in PubMed

Complexities due to single-stranded RNA during antibody detection of genomic rna:dna hybrids BMC Res Notes. 2015 Apr 08; 8:127. . View in PubMed

Human lymphoid translocation fragile zones are hypomethylated and have accessible chromatin Mol Cell Biol. 2015 Apr; 35(7):1209-22. . View in PubMed

Histone methylation and V(D)J recombination Int J Hematol. 2014 Sep; 100(3):230-7. . View in PubMed

Non-homologous end joining often uses microhomology: implications for alternative end joining DNA Repair (Amst). 2014 May; 17:74-80. . View in PubMed

Modeling of the RAG reaction mechanism Cell Rep. 2014 Apr 24; 7(2):307-15. . View in PubMed

Evidence that the DNA endonuclease ARTEMIS also has intrinsic 5'-exonuclease activity J Biol Chem. 2014 Mar 14; 289(11):7825-34. . View in PubMed

Reproducibility and reliability of SNP analysis using human cellular DNA at or near nanogram levels BMC Res Notes. 2013 Dec 06; 6:515. . View in PubMed

Detection and characterization of R-loops at the murine immunoglobulin Sa region Mol Immunol. 2013 Jun; 54(2):208-16. . View in PubMed

BCL6 breaks occur at different AID sequence motifs in Ig-BCL6 and non-Ig-BCL6 rearrangements Blood. 2013 May 30; 121(22):4551-4. . View in PubMed

Large chromosome deletions, duplications, and gene conversion events accumulate with age in normal human colon crypts Aging Cell. 2013 Apr; 12(2):269-79. . View in PubMed

Both CpG methylation and activation-induced deaminase are required for the fragility of the human bcl-2 major breakpoint region: implications for the timing of the breaks in the t(14;18) translocation Mol Cell Biol. 2013 Mar; 33(5):947-57. . View in PubMed

A noncatalytic function of the ligation complex during nonhomologous end joining J Cell Biol. 2013 Jan 21; 200(2):173-86. . View in PubMed

IgH partner breakpoint sequences provide evidence that AID initiates t(11;14) and t(8;14) chromosomal breaks in mantle cell and Burkitt lymphomas Blood. 2012 Oct 04; 120(14):2864-7. . View in PubMed

Mechanistic basis for RAG discrimination between recombination sites and the off-target sites of human lymphomas Mol Cell Biol. 2012 Jan; 32(2):365-75. . View in PubMed

Polynucleotide kinase and aprataxin-like forkhead-associated protein (PALF) acts as both a single-stranded DNA endonuclease and a single-stranded DNA 3' exonuclease and can participate in DNA end joining in a biochemical system J Biol Chem. 2011 Oct 21; 286(42):36368-77. . View in PubMed

Formation of a G-quadruplex at the BCL2 major breakpoint region of the t(14;18) translocation in follicular lymphoma Nucleic Acids Res. 2011 Feb; 39(3):936-48. . View in PubMed

Is there any genetic instability in human cancer? DNA Repair (Amst). 2010 Aug 05; 9(8):858; discussion 859-60.. View in PubMed

DNA-PKcs regulates a single-stranded DNA endonuclease activity of Artemis DNA Repair (Amst). 2010 Apr 04; 9(4):429-37. . View in PubMed

NHEJ and its backup pathways in chromosomal translocations Nat Struct Mol Biol. 2010 Apr; 17(4):393-5. . View in PubMed

Cytosines, but not purines, determine recombination activating gene (RAG)-induced breaks on heteroduplex DNA structures: implications for genomic instability J Biol Chem. 2010 Mar 05; 285(10):7587-97. . View in PubMed

Mechanisms of chromosomal rearrangement in the human genome BMC Genomics. 2010 Feb 10; 11 Suppl 1:S1. . View in PubMed

Nonhomologous DNA end joining (NHEJ) and chromosomal translocations in humans Subcell Biochem. 2010; 50:279-96. . View in PubMed

Competition between the RNA transcript and the nontemplate DNA strand during R-loop formation in vitro: a nick can serve as a strong R-loop initiation site Mol Cell Biol. 2010 Jan; 30(1):146-59. . View in PubMed

H3K4me3 stimulates the V(D)J RAG complex for both nicking and hairpinning in trans in addition to tethering in cis: implications for translocations Mol Cell. 2009 Jun 12; 34(5):535-44. . View in PubMed

G clustering is important for the initiation of transcription-induced R-loops in vitro, whereas high G density without clustering is sufficient thereafter Mol Cell Biol. 2009 Jun; 29(11):3124-33. . View in PubMed

Conformational variants of duplex DNA correlated with cytosine-rich chromosomal fragile sites J Biol Chem. 2009 Mar 13; 284(11):7157-64. . View in PubMed

A histidine in the beta-CASP domain of Artemis is critical for its full in vitro and in vivo functions DNA Repair (Amst). 2009 Feb 01; 8(2):202-8. . View in PubMed

Human chromosomal translocations at CpG sites and a theoretical basis for their lineage and stage specificity Cell. 2008 Dec 12; 135(6):1130-42. . View in PubMed

A biochemically defined system for coding joint formation in V(D)J recombination Mol Cell. 2008 Aug 22; 31(4):485-97. . View in PubMed

FACT-mediated exchange of histone variant H2AX regulated by phosphorylation of H2AX and ADP-ribosylation of Spt16 Mol Cell. 2008 Apr 11; 30(1):86-97. . View in PubMed

DNA-PKcs at 7 angstrom: insights for DNA repair Structure. 2008 Mar; 16(3):334-6. . View in PubMed

RAGs found "not guilty": cleared by DNA evidence Blood. 2008 Feb 15; 111(4):1750. . View in PubMed

Mechanistic flexibility as a conserved theme across 3 billion years of nonhomologous DNA end-joining Genes Dev. 2008 Feb 15; 22(4):411-5. . View in PubMed

Mechanism of R-loop formation at immunoglobulin class switch sequences Mol Cell Biol. 2008 Jan; 28(1):50-60. . View in PubMed

Flexibility in the order of action and in the enzymology of the nuclease, polymerases, and ligase of vertebrate non-homologous DNA end joining: relevance to cancer, aging, and the immune system Cell Res. 2008 Jan; 18(1):125-33. . View in PubMed

Mechanistic aspects of lymphoid chromosomal translocations J Natl Cancer Inst Monogr. 2008; (39):8-11. . View in PubMed

Sequence dependence of chromosomal R-loops at the immunoglobulin heavy-chain Smu class switch region Mol Cell Biol. 2007 Aug; 27(16):5921-32. . View in PubMed

DNA structure and human diseases Front Biosci. 2007 May 01; 12:4402-8. . View in PubMed

Length-dependent binding of human XLF to DNA and stimulation of XRCC4DNA ligase IV activity. J Biol Chem. 2007 Apr 13; 282(15):11155-62. . View in PubMed

Extent to which hairpin opening by the Artemis:DNA-PKcs complex can contribute to junctional diversity in V(D)J recombination Nucleic Acids Res. 2007; 35(20):6917-23. . View in PubMed

DNA-PKcs dependence of Artemis endonucleolytic activity, differences between hairpins and 5' or 3' overhangs J Biol Chem. 2006 Nov 10; 281(45):33900-9. . View in PubMed

Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations DNA Repair (Amst). 2006 Sep 08; 5(9-10):1234-45. . View in PubMed

DNA structures at chromosomal translocation sites Bioessays. 2006 May; 28(5):480-94. . View in PubMed

Downstream boundary of chromosomal R-loops at murine switch regions: implications for the mechanism of class switch recombination Proc Natl Acad Sci U S A. 2006 Mar 28; 103(13):5030-5. . View in PubMed

Hybrid joint formation in human V(D)J recombination requires nonhomologous DNA end joining DNA Repair (Amst). 2006 Feb 03; 5(2):278-85. . View in PubMed

Analysis of non-B DNA structure at chromosomal sites in the mammalian genome Methods Enzymol. 2006; 409:301-16. . View in PubMed

In vitro nonhomologous DNA end joining system Methods Enzymol. 2006; 408:502-10. . View in PubMed

Detection and structural analysis of R-loops Methods Enzymol. 2006; 409:316-29. . View in PubMed

Repair of double-strand DNA breaks by the human nonhomologous DNA end joining pathway: the iterative processing model Cell Cycle. 2005 Sep; 4(9):1193-200. . View in PubMed

Both V(D)J coding ends but neither signal end can recombine at the bcl-2 major breakpoint region, and the rejoining is ligase IV dependent Mol Cell Biol. 2005 Aug; 25(15):6475-84. . View in PubMed

Double-strand break formation by the RAG complex at the bcl-2 major breakpoint region and at other non-B DNA structures in vitro Mol Cell Biol. 2005 Jul; 25(14):5904-19. . View in PubMed

Evidence for a triplex DNA conformation at the bcl-2 major breakpoint region of the t(14;18) translocation J Biol Chem. 2005 Jun 17; 280(24):22749-60. . View in PubMed

Omenn syndrome due to ARTEMIS mutations Blood. 2005 Jun 01; 105(11):4179-86. . View in PubMed

Fine-structure analysis of activation-induced deaminase accessibility to class switch region R-loops Mol Cell Biol. 2005 Mar; 25(5):1730-6. . View in PubMed

Generation and characterization of endonuclease G null mice Mol Cell Biol. 2005 Jan; 25(1):294-302. . View in PubMed

Genetic interactions between BLM and DNA ligase IV in human cells J Biol Chem. 2004 Dec 31; 279(53):55433-42. . View in PubMed

A biochemically defined system for mammalian nonhomologous DNA end joining Mol Cell. 2004 Dec 03; 16(5):701-13. . View in PubMed

DNA damage and aging Mech Ageing Dev. 2004 Jun; 125(6):405-16. . View in PubMed

Chromosomal translocations and non-B DNA structures in the human genome Cell Cycle. 2004 Jun; 3(6):762-8. . View in PubMed

Functional and biochemical dissection of the structure-specific nuclease ARTEMIS EMBO J. 2004 May 05; 23(9):1987-97. . View in PubMed

A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex Nature. 2004 Mar 04; 428(6978):88-93. . View in PubMed

DNA substrate length and surrounding sequence affect the activation-induced deaminase activity at cytidine J Biol Chem. 2004 Feb 20; 279(8):6496-500. . View in PubMed

Kinetic analysis of the nicking and hairpin formation steps in V(D)J recombination DNA Repair (Amst). 2004 Jan 05; 3(1):67-75. . View in PubMed

Ageing, repetitive genomes and DNA damage Nat Rev Mol Cell Biol. 2004 Jan; 5(1):69-75. . View in PubMed

Developmental retinal apoptosis in Ku86-/- mice DNA Repair (Amst). 2003 Dec 09; 2(12):1429-34. . View in PubMed

Nucleic acid structures and enzymes in the immunoglobulin class switch recombination mechanism DNA Repair (Amst). 2003 Nov 21; 2(11):1163-74. . View in PubMed

Human severe combined immune deficiency and DNA repair Bioessays. 2003 Nov; 25(11):1061-70. . View in PubMed

Mechanism and regulation of human non-homologous DNA end-joining Nat Rev Mol Cell Biol. 2003 Sep; 4(9):712-20. . View in PubMed

R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells Nat Immunol. 2003 May; 4(5):442-51. . View in PubMed

Impact of DNA ligase IV on the fidelity of end joining in human cells Nucleic Acids Res. 2003 Apr 15; 31(8):2157-67. . View in PubMed

Overexpression of Cu/Zn superoxide dismutase is lethal for mice lacking double-strand break repair DNA Repair (Amst). 2003 Mar 01; 2(3):285-94. . View in PubMed

Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia J Biol Chem. 2002 Nov 29; 277(48):46289-97. . View in PubMed

Bidirectional gene organization: a common architectural feature of the human genome Cell. 2002 Jun 28; 109(7):807-9. . View in PubMed

Binding of inositol hexakisphosphate (IP6) to Ku but not to DNA-PKcs J Biol Chem. 2002 Mar 29; 277(13):10756-9. . View in PubMed

Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination Cell. 2002 Mar 22; 108(6):781-94. . View in PubMed

Oxygen metabolism causes chromosome breaks and is associated with the neuronal apoptosis observed in DNA double-strand break repair mutants Curr Biol. 2002 Mar 05; 12(5):397-402. . View in PubMed

Analysis of the kinetic and equilibrium binding of Ku protein to DNA J Theor Biol. 2002 Jan 07; 214(1):85-97. . View in PubMed

Antibody diversity: a link between switching and hypermutation Curr Biol. 2000 Nov 02; 10(21):R798-800. . View in PubMed

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