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Publications

Complete List of Published Work in My Bibliography: https://www.ncbi.nlm.nih.gov/myncbi/1D_z98anQtR5v/bibliography/public/

Reviews:

Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008;26:261-92. PubMed PMID: 18370922; PubMed Central PMCID: PMC2707252. Schrader CE, Guikema JE, Wu X, Stavnezer J. The roles of APE1, APE2, DNA polymerase beta and mismatch repair in creating S region DNA breaks during antibody class switch. Philos Trans R Soc Lond B Biol Sci. 2009 Mar 12;364(1517):645-52. PubMed PMID: 19010771; PubMed Central PMCID: PMC2660920.

Selected publications by topic:

The Role of Mismatch Repair (MMR) in Class Switch Recombination (CSR). I was among the first to identify a role for mismatch repair proteins in CSR. This was prior to the discovery of AID, and actually began the intense focus on the role of DNA repair proteins in CSR that continues to this day. I subsequently showed that MMR functions to generate double-strand DNA breaks in Switch regions during class switching. The model we proposed for this mechanism is widely accepted and cited.

Schrader CE, Edelmann W, Kucherlapati R, Stavnezer J. Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes. J Exp Med. 1999 Aug 2;190(3):323-30. PubMed PMID: 10430621; PubMed Central PMCID: PMC2195591.

Schrader CE, Vardo J, Stavnezer J. Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. J Exp Med. 2002 Feb 4;195(3):367-73. PubMed PMID: 11828012; PubMed Central PMCID: PMC2193596.

Min IM, Schrader CE, Vardo J, Luby TM, D'Avirro N, Stavnezer J, Selsing E. The Smu tandem repeat region is critical for Ig isotype switching in the absence of Msh2. Immunity. 2003 Oct;19(4):515-24. PubMed PMID: 14563316.

Stavnezer J, Schrader CE. Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination. Trends Genet. 2006 Jan;22(1):23-8. PubMed PMID: 16309779.

Mechanism of DSB formation during CSR. I went on to show that the DNA breaks made during CSR are dependent on AID and UNG in a paper that was on the list of the top ten most read papers for the month at JEM. I adapted a ligation-mediated PCR technique that permitted semi-quantitative analysis of switch region double-strand breaks, and validated the system by cloning and sequencing to identify the nucleotide at which the breaks occurred. I showed the timecourse of break formation, that the breaks occur in the G1 phase of the cell cycle and depend on mismatch repair, and that p53 is not responsible for restricting the breaks to G1 phase. More recently we showed that ATM promotes AID activity at the acceptor switch region, and in its absence, breaks accumulate at the donor switch region, Smu. In collaboration with Dr. Stavnezer, we identified sites of off-target DSBs induced by AID in cultured B cells using NBS1-ChIP-Seq.

Guikema JE, Linehan EK, Tsuchimoto D, Nakabeppu Y, Strauss PR, Stavnezer J, Schrader CE. APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. J Exp Med. 2007 Nov 26;204(12):3017-26. PubMed PMID: 18025127; PubMed Central PMCID: PMC2118529.

Schrader CE, Linehan EK, Mochegova SN, Woodland RT, Stavnezer J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J Exp Med. 2005 Aug 15;202(4):561-8. PubMed PMID: 16103411; PubMed Central PMCID: PMC2212854.

Schrader CE, Guikema JE, Linehan EK, Selsing E, Stavnezer J. Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. J Immunol. 2007 Nov 1;179(9):6064-71. PubMed PMID: 17947680.

Khair L, Guikema JE, Linehan EK, Ucher AJ, Leus NG, Ogilvie C, Lou Z, Schrader CE, Stavnezer J. ATM increases activation-induced cytidine deaminase activity at downstream S regions during class- switch recombination. J Immunol. 2014 May 15;192(10):4887-96. PubMed PMID: 24729610; PubMed Central PMCID: PMC4049217.

Khair L, Baker RE, Linehan EK, Schrader CE, Stavnezer J. Nbs1 ChIP-Seq Identifies Off-Target DNA Double-Strand Breaks Induced by AID in Activated Splenic B Cells. PLoS Genet. 2015 Aug;11(8):e1005438. PubMed PMID: 26263206; PubMed Central PMCID: PMC4532491.

AP Endonucleases in CSR and SHM. I then identified a surprising role for a little known endonuclease, AP endonuclease 2 (APE2), in addition to its homologue, APE1, in making the breaks required for class switching. I have since described important roles for APE2 in B lymphocyte development and in promoting germinal center B cell survival. A role for APE2 in introducing DNA breaks during CSR was surprising and controversial, and seemed unlikely because APE2 has such weak endonuclease activity in vitro. Having continued trying to understand the role of this little-known protein in repair of AID-induced lesions, I recently made the startling discovery that expression of the efficient homologue, APE1, is dramatically reduced in germinal centers, where APE2 is highly expressed. I showed that APE2 promotes somatic hypermutation in the germinal center, and proposed that down-regulation of APE1, and the alternative expression of APE2 (the less efficient homolog), is a cause of error-prone repair of AID-induced lesions in B cells.

Stavnezer J, Linehan EK, Thompson MR, Habboub G, Ucher AJ, Kadungure T, Tsuchimoto D, Nakabeppu Y, Schrader CE. Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation. Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9217-22. PubMed PMID: 24927551; PubMed Central PMCID: PMC4078814.

Guikema JE, Gerstein RM, Linehan EK, Cloherty EK, Evan-Browning E, Tsuchimoto D, Nakabeppu Y, Schrader CE. Apurinic/apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge. J Immunol. 2011 Feb 15;186(4):1943-50. PubMed PMID: 21228350; PubMed Central PMCID: PMC4041036.

Guikema JE, Linehan EK, Esa N, Tsuchimoto D, Nakabeppu Y, Woodland RT, Schrader CE. Apurinic/apyrimidinic endonuclease 2 regulates the expansion of germinal centers by protecting against activation-induced cytidine deaminase-independent DNA damage in B cells. J Immunol. 2014 Jul 15;193(2):931-9. PubMed PMID: 24935922; PubMed Central PMCID: PMC4105697.