Keck School Faculty

Michael R. Lieber

Michael R. Lieber

Professor of Pathology
Rita and Edward Polusky Chair in Basic Cancer Research
Pathology
NTT 1441 Eastlake Ave Health Sciences Campus Los Angeles

The mechanisms of human lymphoid chromosomal translocations and their medical relevance Crit Rev Biochem Mol Biol. 2022 06; 57(3):227-243. . View in PubMed

The mRNA tether model for activation-induced deaminase and its relevance for Ig somatic hypermutation and class switch recombination DNA Repair (Amst). 2022 02; 110:103271. . View in PubMed

Structural analysis of the basal state of the Artemis:DNA-PKcs complex Nucleic Acids Res. 2022 07 22; 50(13):7697-7720. . View in PubMed

Nonhomologous DNA end joining of nucleosomal substrates in a purified system DNA Repair (Amst). 2021 10; 106:103193. . View in PubMed

Preclinical Evaluation of a Novel Dual Targeting PI3Kd/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia Front Oncol. 2021; 11:766888. . View in PubMed

Mechanistic basis for chromosomal translocations at the E2A gene and its broader relevance to human B cell malignancies Cell Rep. 2021 07 13; 36(2):109387. . View in PubMed

Temporally uncoupled signal and coding joint formation in human V(D)J recombination Mol Immunol. 2020 12; 128:227-234. . View in PubMed

The molecular basis and disease relevance of non-homologous DNA end joining Nat Rev Mol Cell Biol. 2020 12; 21(12):765-781. . View in PubMed

DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination Mol Immunol. 2020 04; 120:93-100. . View in PubMed

Clinical Evaluation and Utilization of Multiple Molecular In Vitro Diagnostic Assays for the Detection of SARS-CoV-2 Am J Clin Pathol. 2020 07 07; 154(2):201-207. . View in PubMed

NAD+ is not utilized as a co-factor for DNA ligation by human DNA ligase IV Nucleic Acids Res. 2020 12 16; 48(22):12746-12750. . View in PubMed

Structural analysis of the catalytic domain of Artemis endonuclease/SNM1C reveals distinct structural features J Biol Chem. 2020 08 28; 295(35):12368-12377. . View in PubMed

Polymerase µ in non-homologous DNA end joining: importance of the order of arrival at a double-strand break in a purified system Nucleic Acids Res. 2020 04 17; 48(7):3605-3618. . View in PubMed

Constitutively active Artemis nuclease recognizes structures containing single-stranded DNA configurations DNA Repair (Amst). 2019 11; 83:102676. . View in PubMed

Current insights into the mechanism of mammalian immunoglobulin class switch recombination Crit Rev Biochem Mol Biol. 2019 08; 54(4):333-351. . View in PubMed

Transposons to V(D)J Recombination: Evolution of the RAG Reaction Trends Immunol. 2019 08; 40(8):668-670. . 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. 2019 03; 60(3):437-438. . View in PubMed

Structural evidence for an in trans base selection mechanism involving Loop1 in polymerase µ at an NHEJ double-strand break junction J Biol Chem. 2019 07 05; 294(27):10579-10595. . View in PubMed

AID and Reactive Oxygen Species Can Induce DNA Breaks within Human Chromosomal Translocation Fragile Zones Mol Cell. 2019 02 07; 73(3):639. . View in PubMed

The essential elements for the noncovalent association of two DNA ends during NHEJ synapsis Nat Commun. 2019 08 09; 10(1):3588. . 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

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 07; 59(7):1014-1016. . View in PubMed

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

DNA Repair After Exposure to Ionizing Radiation Is Not Error-Free J Nucl Med. 2018 02; 59(2):348. . 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

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

Structural step forward for NHEJ Cell Res. 2017 11; 27(11):1304-1306. . 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

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

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

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

Structure-Specific nuclease activities of Artemis and the Artemis: DNA-PKcs complex Nucleic Acids Res. 2016 06 20; 44(11):4991-7. . 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

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

Unifying the DNA end-processing roles of the artemis nuclease: Ku-dependent artemis resection at blunt DNA ends J Biol Chem. 2015 Oct 02; 290(40):24036-50. . View in PubMed

The repetitive portion of the Xenopus IgH Mu switch region mediates orientation-dependent class switch recombination Mol Immunol. 2015 Oct; 67(2 Pt B):524-31. . 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

The role of G-density in switch region repeats for immunoglobulin class switch recombination Nucleic Acids Res. 2014 Dec 01; 42(21):13186-93. . View in PubMed

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

The strength of an Ig switch region is determined by its ability to drive R loop formation and its number of WGCW sites Cell Rep. 2014 Jul 24; 8(2):557-69. . 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):307-315. . 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

t(X;14)(p22;q32)/t(Y;14)(p11;q32) CRLF2-IGH translocations from human B-lineage ALLs involve CpG-type breaks at CRLF2, but CRLF2/P2RY8 intrachromosomal deletions do not Blood. 2010 Sep 16; 116(11):1993-4. . View in PubMed

SnapShot: Nonhomologous DNA end joining (NHEJ)Cell. 2010 Aug 06; 142(3):496-496. e1. . 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

The t(14;18)(q32;q21)/IGH-MALT1 translocation in MALT lymphomas is a CpG-type translocation, but the t(11;18)(q21;q21)/API2-MALT1 translocation in MALT lymphomas is not Blood. 2010 Apr 29; 115(17):3640-1; author reply 3641-2. . 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

Successful treatment of calcific uremic arteriolopathy in a pediatric dialysis patient Pediatr Nephrol. 2010 Feb; 25(2):357-62. . View in PubMed

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

The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway Annu Rev Biochem. 2010; 79:181-211. . 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

The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia Cancer Cell. 2009 Sep 08; 16(3):232-45. . 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

Unexpected complexity at breakpoint junctions in phenotypically normal individuals and mechanisms involved in generating balanced translocations t(1;22)(p36;q13) Genome Res. 2008 Nov; 18(11):1733-42. . View in PubMed

A biochemically defined system for coding joint formation in V(D)J recombination Mol Cell. 2008 Aug 22; 31(4):485-497. . 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

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

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

The mechanism of human nonhomologous DNA end joining J Biol Chem. 2008 Jan 04; 283(1):1-5. . View in PubMed

Turning anti-ageing genes against cancer Nat Rev Mol Cell Biol. 2008 11; 9(11):903-10. . View in PubMed

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

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

The structure-specific nicking of small heteroduplexes by the RAG complex: implications for lymphoid chromosomal translocations DNA Repair (Amst). 2007 Jun 01; 6(6):751-9. . 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

XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps EMBO J. 2007 Feb 21; 26(4):1010-23. . View in PubMed

Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence Nucleic Acids Res. 2007; 35(17):5755-62. . 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

Hyperbaric oxygen in treatment of neonatal arterial thromboembolism of lower extremities J Perinatol. 2006 Dec; 26(12):777-9. . 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

The polymerases for V(D)J recombination Immunity. 2006 Jul; 25(1):7-9. . 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

Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV Eur J Immunol. 2006 Jan; 36(1):224-35. . View in PubMed

The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis J Biol Chem. 2005 Oct 07; 280(40):33839-46. . 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

The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps DNA Repair (Amst). 2005 Jul 12; 4(7):845-51. . 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

The efficacy of hyperbaric oxygen therapy in the treatment of radiation-induced late side effects Int J Radiat Oncol Biol Phys. 2004 Nov 01; 60(3):871-8. . View in PubMed

Stability and strand asymmetry in the non-B DNA structure at the bcl-2 major breakpoint region J Biol Chem. 2004 Oct 29; 279(44):46213-25. . View in PubMed

The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination DNA Repair (Amst). 2004 Aug-Sep; 3(8-9):817-26. . 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

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

The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a Proc Natl Acad Sci U S A. 2002 Dec 24; 99(26):16916-21. . View in PubMed

The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants DNA Repair (Amst). 2002 Dec 05; 1(12):1017-26. . 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

The cleavage efficiency of the human immunoglobulin heavy chain VH elements by the RAG complex: implications for the immune repertoire J Biol Chem. 2002 Feb 15; 277(7):5040-6. . 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

Two overlapping divergent transcription units in the human genome: the FEN1/C11orf10 locus OMICS. 2002; 6(3):273-9. . View in PubMed

Transcription-dependent R-loop formation at mammalian class switch sequences EMBO J. 2001 Sep 01; 19(17):4855. . View in PubMed

DNA length-dependent cooperative interactions in the binding of Ku to DNA Biochemistry. 2001 Aug 14; 40(32):9638-46. . View in PubMed

Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints J Biol Chem. 2001 Aug 03; 276(31):29126-33. . View in PubMed

Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection EMBO J. 2001 Jun 15; 20(12):3272-81. . View in PubMed

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

The nicking step in V(D)J recombination is independent of synapsis: implications for the immune repertoire Mol Cell Biol. 2000 Nov; 20(21):7914-21. . View in PubMed

The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts Curr Biol. 1999 Dec 16-30; 9(24):1501-4. . View in PubMed

Mechanistic basis for coding end sequence effects in the initiation of V(D)J recombination Mol Cell Biol. 1999 Dec; 19(12):8094-102. . View in PubMed

Efficient processing of DNA ends during yeast nonhomologous end joiningEvidence for a DNA polymerase beta (Pol4)-dependent pathway. J Biol Chem. 1999 Aug 13; 274(33):23599-609. . View in PubMed

A role for FEN-1 in nonhomologous DNA end joining: the order of strand annealing and nucleolytic processing events Proc Natl Acad Sci U S A. 1999 Feb 16; 96(4):1303-8. . View in PubMed

The biochemistry and biological significance of nonhomologous DNA end joining: an essential repair process in multicellular eukaryotes Genes Cells. 1999 Feb; 4(2):77-85. . View in PubMed

The RAG-HMG1 complex enforces the 12/23 rule of V(D)J recombination specifically at the double-hairpin formation step Mol Cell Biol. 1998 Nov; 18(11):6408-15. . View in PubMed

Warner-Lambert/Parke-Davis Award LecturePathological and physiological double-strand breaks: roles in cancer, aging, and the immune system. Am J Pathol. 1998 Nov; 153(5):1323-32. . View in PubMed

Productive and nonproductive complexes of Ku and DNA-dependent protein kinase at DNA termini Mol Cell Biol. 1998 Oct; 18(10):5908-20. . View in PubMed

DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes Mol Cell. 1998 Oct; 2(4):477-84. . View in PubMed

Requirement for an interaction of XRCC4 with DNA ligase IV for wild-type V(D)J recombination and DNA double-strand break repair in vivo J Biol Chem. 1998 Sep 18; 273(38):24708-14. . View in PubMed

DNA-PK is essential only for coding joint formation in V(D)J recombination Nucleic Acids Res. 1998 Sep 01; 26(17):3944-8. . View in PubMed

DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains Curr Biol. 1998 Jul 16; 8(15):873-6. . View in PubMed

Antigen receptor gene rearrangement Curr Opin Immunol. 1998 Apr; 10(2):172-80. . View in PubMed

V(D)J recombination activity in human hematopoietic cells: correlation with developmental stage and genome stability Eur J Immunol. 1998 Jan; 28(1):351-8. . View in PubMed

Interaction between DNA-dependent protein kinase and a novel protein, KIP Mutat Res. 1997 Oct; 385(1):13-20. . View in PubMed

Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy studies EMBO J. 1997 Aug 15; 16(16):5098-112. . View in PubMed

Yeast DNA ligase IV mediates non-homologous DNA end joining Nature. 1997 Jul 31; 388(6641):495-8. . View in PubMed

Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells Nature. 1997 Jul 31; 388(6641):492-5. . View in PubMed

A complex of RAG-1 and RAG-2 proteins persists on DNA after single-strand cleavage at V(D)J recombination signal sequences Nucleic Acids Res. 1997 Apr 01; 25(7):1375-82. . View in PubMed

The role of recombination signal sequences in the preferential joining by deletion in DH-JH recombination and in the ordered rearrangement of the IgH locus Int Immunol. 1997 Apr; 9(4):515-22. . View in PubMed

The FEN-1 family of structure-specific nucleases in eukaryotic DNA replication, recombination and repair Bioessays. 1997 Mar; 19(3):233-40. . View in PubMed

Tying loose ends: roles of Ku and DNA-dependent protein kinase in the repair of double-strand breaks Curr Opin Genet Dev. 1997 Feb; 7(1):99-104. . View in PubMed

RAG mutations in human B cell-negative SCID Science. 1996 Oct 04; 274(5284):97-9. . View in PubMed

Protein-protein and protein-DNA interaction regions within the DNA end-binding protein Ku70-Ku86 Mol Cell Biol. 1996 Sep; 16(9):5186-93. . View in PubMed

Processing of branched DNA intermediates by a complex of human FEN-1 and PCNA Nucleic Acids Res. 1996 Jun 01; 24(11):2036-43. . View in PubMed

Asymmetric mutation around the recombination break point of immunoglobulin class switch sequences on extrachromosomal substrates Nucleic Acids Res. 1996 Jun 01; 24(11):2104-11. . View in PubMed

Immunoglobulin diversity: rearranging by cutting and repairing Curr Biol. 1996 Feb 01; 6(2):134-6. . View in PubMed

Transcription targets recombination at immunoglobulin switch sequences in a strand-specific manner Curr Top Microbiol Immunol. 1996; 217:171-89. . View in PubMed

Mechanistic constraints on diversity in human V(D)J recombination Mol Cell Biol. 1996 Jan; 16(1):258-69. . View in PubMed

RNA:DNA complex formation upon transcription of immunoglobulin switch regions: implications for the mechanism and regulation of class switch recombination Nucleic Acids Res. 1995 Dec 25; 23(24):5006-11. . View in PubMed

Human DNA-activated protein kinase (DNA-PK) is homologous to phosphatidylinositol kinases J Immunol. 1995 Nov 15; 155(10):4529-33. . View in PubMed

Mechanistic properties of immunoglobulin somatic mutation Ann N Y Acad Sci. 1995 Sep 29; 764:187-8. . View in PubMed

Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen J Biol Chem. 1995 Sep 22; 270(38):22109-12. . View in PubMed

Strand specificity in the transcriptional targeting of recombination at immunoglobulin switch sequences Proc Natl Acad Sci U S A. 1995 Jun 06; 92(12):5625-9. . View in PubMed

The scid factor on human chromosome 8 restores V(D)J recombination in addition to double-strand break repair Cancer Res. 1995 Apr 15; 55(8):1774-9. . View in PubMed

DNA structural elements required for FEN-1 binding J Biol Chem. 1995 Mar 03; 270(9):4503-8. . View in PubMed

Treatment with finasteride following radical prostatectomy for prostate cancer Urology. 1995 Mar; 45(3):491-7. . View in PubMed

Sequence of human FEN-1, a structure-specific endonuclease, and chromosomal localization of the gene (FEN1) in mouse and human Genomics. 1995 Jan 01; 25(1):220-5. . View in PubMed

Restoration of X-ray resistance and V(D)J recombination in mutant cells by Ku cDNA Science. 1994 Oct 14; 266(5183):288-91. . View in PubMed

Distinct roles for RAG-1 in the initiation of V(D)J recombination and in the resolution of coding ends J Biol Chem. 1994 Sep 02; 269(35):22188-92. . View in PubMed

Analysis of individual immunoglobulin lambda light chain genes amplified from single cells is inconsistent with variable region gene conversion in germinal-center B cell somatic mutation Eur J Immunol. 1994 Aug; 24(8):1816-22. . View in PubMed

Functional domains within FEN-1 and RAD2 define a family of structure-specific endonucleases: implications for nucleotide excision repair Genes Dev. 1994 Jun 01; 8(11):1344-55. . View in PubMed

The mechanism of V(D)J recombination: site-specificity, reaction fidelity and immunologic diversity Semin Immunol. 1994 Jun; 6(3):143-53. . View in PubMed

Chimeric molecules created by gene amplification interfere with the analysis of somatic hypermutation of murine immunoglobulin genes Gene. 1994 May 16; 142(2):279-83. . View in PubMed

Transcription, topoisomerases and recombination Experientia. 1994 Mar 15; 50(3):261-9. . View in PubMed

The characterization of a mammalian DNA structure-specific endonuclease EMBO J. 1994 Mar 01; 13(5):1235-46. . View in PubMed

V(D)J recombination in ataxia telangiectasia, Bloom's syndrome, and a DNA ligase I-associated immunodeficiency disorder J Biol Chem. 1993 Sep 25; 268(27):20105-9. . View in PubMed

Unequal signal and coding joint formation in human V(D)J recombination Mol Cell Biol. 1993 Jul; 13(7):3900-6. . View in PubMed

Coding end sequence can markedly affect the initiation of V(D)J recombination Genes Dev. 1993 Jul; 7(7B):1459-69. . View in PubMed

Extent to which homology can constrain coding exon junctional diversity in V(D)J recombination Nature. 1993 Jun 17; 363(6430):625-7. . View in PubMed

V(D)J recombination in mammalian cell mutants defective in DNA double-strand break repair Mol Cell Biol. 1993 Jun; 13(6):3464-71. . View in PubMed

V(D)J recombination: signal and coding joint resolution are uncoupled and depend on parallel synapsis of the sites Mol Cell Biol. 1993 Mar; 13(3):1363-70. . View in PubMed

Lymphoid V(D)J recombinationFunctional analysis of the spacer sequence within the recombination signal. J Biol Chem. 1993 Feb 15; 268(5):3180-3. . View in PubMed

DEAE-dextran enhances electroporation of mammalian cells Nucleic Acids Res. 1992 Dec 25; 20(24):6739-40. . View in PubMed

Analysis of the defect in DNA end joining in the murine scid mutation Mol Cell Biol. 1992 Oct; 12(10):4758-68. . View in PubMed

The mechanism of V(D)J recombination: a balance of diversity, specificity, and stability Cell. 1992 Sep 18; 70(6):873-6. . View in PubMed

V(D)J recombination on minichromosomes is not affected by transcription J Biol Chem. 1992 Aug 05; 267(22):15613-9. . View in PubMed

The basis for the mechanistic bias for deletional over inversional V(D)J recombination Genes Dev. 1992 Aug; 6(8):1553-61. . View in PubMed

CpG methylated minichromosomes become inaccessible for V(D)J recombination after undergoing replication EMBO J. 1992 Jan; 11(1):315-25. . View in PubMed

Replication, transcription, CpG methylation and DNA topology in V(D)J recombination Curr Top Microbiol Immunol. 1992; 182:125-35. . View in PubMed

Site-specific recombination in the immune system FASEB J. 1991 Nov; 5(14):2934-44. . View in PubMed

V(D)J recombination: evidence that a replicative mechanism is not required Mol Cell Biol. 1991 Aug; 11(8):3972-7. . View in PubMed

V(D)J recombination: a functional definition of the joining signals Genes Dev. 1989 Jul; 3(7):1053-61. . View in PubMed

Hemolytic holes in human erythrocyte membrane ghosts Methods Enzymol. 1989; 173:356-67. . View in PubMed

Abnormal V(D)J recombination in murine severe combined immune deficiency: absence of coding joints and formation of alternative productsAbnormal V(D)J recombination in murine severe combined immune deficiency: absence of coding joints and formation of alternative products. Curr Top Microbiol Immunol. 1989; 152:69-75. . View in PubMed

Lymphoid V(D)J recombination: nucleotide insertion at signal joints as well as coding joints Proc Natl Acad Sci U S A. 1988 Nov; 85(22):8588-92. . View in PubMed

The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination Cell. 1988 Oct 07; 55(1):7-16. . View in PubMed

Studies of V(D)J recombination with extrachromosomal substrates Curr Top Microbiol Immunol. 1988; 137:94-9. . View in PubMed

Developmental stage specificity of the lymphoid V(D)J recombination activity Genes Dev. 1987 Oct; 1(8):751-61. . View in PubMed

The mechanism of osmotic transfection of avian embryonic erythrocytes: analysis of a system for studying developmental gene expression J Cell Biol. 1987 Sep; 105(3):1055-65. . View in PubMed

Extrachromosomal DNA substrates in pre-B cells undergo inversion or deletion at immunoglobulin V-(D)-J joining signals Cell. 1987 Jun 19; 49(6):775-83. . View in PubMed

DNA sequence of the 5' flanking region of the human interleukin 2 gene: homologies with adult T-cell leukemia virus Nucleic Acids Res. 1984 Jun 25; 12(12):5005-13. . View in PubMed

Lifespan changes in the index of cephalization Exp Aging Res. 1984; 10(3):127-35. . View in PubMed

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.
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