Douglas K. Bishop

Research Summary
Homologous recombination repairs DNA damage, facilitates DNA replication, and creates the physical connections between chromosomes needed for reductional chromosome segregation during meiosis. We study two key recombination proteins, Dmc1 and Rad51 that are related to the central bacterial recombination protein, RecA. The mechanisms of recombinational repair of damage induced double strand breaks in DNA (DSBs) and the mechanism of meiotic recombination are very closely related in terms of the DNA intermediates that form; DSBs are normal intermediates in most or all meiotic recombination. There are, however critical differences in how meiotic recombination is regulated as compared to mitotic recombinational repair. Our research is directed at understanding how Dmc1's function is specialized for meiosis, how the functions of Rad51 and Dmc1 differ, how the two proteins interact with one another during meiosis, and how the two proteins interact with components of the synaptonemal complex, a meiosis-specific chromosome scaffold. Our studies show that Rad51, which serves as the central “recombinase” in mitotic cells, is converted to a Dmc1 accessory protein in meiosis. Our current approaches to understanding Rad51 and Dmc1 function include biochemical reconstitution of Dmc1 activity. This work currently involves 7 meiotic recombination proteins. We were first to show that recombination proteins can be detected at multiple subnuclear sites during recombination using immunostaining techniques. We have used cytological methods in the past to identify proteins required for recruitment of recombinase to double strand break sites in mitotic and meiotic cells. These regulators include the breast cancer susceptibility genes BRCA1 and BRCA2, which promote the assembly of recombination complexes, and RAD54 family translocases, which promote disassembly. We recently began to focus our cytological efforts on super-resolution light microscopy methods including STORM and STED. These methods are shedding new light on the architecture of the recombinosome. Finally we use molecular genetic techniques that allow detection of DNA recombination intermediates to study the mechanism that regulate meiotic recombination in living cells.
meiosis, homologous recombination, homology-directed DNA repair, gene targeting, Rad51, Dmc1, RecA
  • Amherst College, Amherst, MA, B.A. Biology 06/1980
  • Harvard University, Cambridge, MA, Ph. D. Cell and Developmental Biology 06/1988
  1. Reitz D, Chan YL, Bishop DK. How strand exchange protein function benefits from ATP hydrolysis. Curr Opin Genet Dev. 2021 12; 71:120-128. View in: PubMed

  2. Billmyre KK, Bravo N??ez MA, Bishop DK, Cole F. Meiosis in Quarantine discussions lead to an action plan to increase diversity and inclusion within the genetics community. PLoS Genet. 2021 07; 17(7):e1009648. View in: PubMed

  3. Pamer EG. Microbial Tuning of the Mammalian Immune System. Trends Mol Med. 2017 05; 23(5):379-380. View in: PubMed

  4. Shinohara M, Bishop DK, Shinohara A. Distinct Functions in Regulation of Meiotic Crossovers for DNA Damage Response Clamp Loader Rad24(Rad17) and Mec1(ATR) Kinase. Genetics. 2019 Dec 01; 213(4):1255-1269. View in: PubMed

  5. Reitz D, Grubb J, Bishop DK. A mutant form of Dmc1 that bypasses the requirement for accessory protein Mei5-Sae3 reveals independent activities of Mei5-Sae3 and Rad51 in Dmc1 filament stability. PLoS Genet. 2019 12; 15(12):e1008217. View in: PubMed

  6. Shinohara M, Bishop DK, Shinohara A. Distinct Functions in Regulation of Meiotic Crossovers for DNA Damage Response Clamp Loader Rad24(Rad17) and Mec1(ATR) Kinase. Genetics. 2019 12; 213(4):1255-1269. View in: PubMed

  7. Mason JM, Chan YL, Weichselbaum RW, Bishop DK. Non-enzymatic roles of human RAD51 at stalled replication forks. Nat Commun. 2019 09 27; 10(1):4410. View in: PubMed

  8. Chan YL, Zhang A, Weissman BP, Bishop DK. RPA resolves conflicting activities of accessory proteins during reconstitution of Dmc1-mediated meiotic recombination. Nucleic Acids Res. 2019 01 25; 47(2):747-761. View in: PubMed

  9. Gataulin DV, Carey JN, Li J, Shah P, Grubb JT, Bishop DK. The ATPase activity of E. coli RecA prevents accumulation of toxic complexes formed by erroneous binding to undamaged double stranded DNA. Nucleic Acids Res. 2018 10 12; 46(18):9510-9523. View in: PubMed

  10. Chan YL, Bishop DK. Purification of Saccharomyces cerevisiae Homologous Recombination Proteins Dmc1 and Rdh54/Tid1 and a Fluorescent D-Loop Assay. Methods Enzymol. 2018; 600:307-320. View in: PubMed

  11. Brown MS, Grubb J, Zhang A, Rust MJ, Bishop DK. Small Rad51 and Dmc1 Complexes Often Co-occupy Both Ends of a Meiotic DNA Double Strand Break. PLoS Genet. 2015 Dec; 11(12):e1005653. View in: PubMed

  12. Grubb J, Brown MS, Bishop DK. Surface Spreading and Immunostaining of Yeast Chromosomes. J Vis Exp. 2015 Aug 09; (102):e53081. View in: PubMed

  13. Tsabar M, Eapen VV, Mason JM, Memisoglu G, Waterman DP, Long MJ, Bishop DK, Haber JE. Caffeine impairs resection during DNA break repair by reducing the levels of nucleases Sae2 and Dna2. Nucleic Acids Res. 2015 Aug 18; 43(14):6889-901. View in: PubMed

  14. Tsabar M, Mason JM, Chan YL, Bishop DK, Haber JE. Caffeine inhibits gene conversion by displacing Rad51 from ssDNA. Nucleic Acids Res. 2015 Aug 18; 43(14):6902-18. View in: PubMed

  15. Mason JM, Dusad K, Wright WD, Grubb J, Budke B, Heyer WD, Connell PP, Weichselbaum RR, Bishop DK. RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells. Nucleic Acids Res. 2015 Mar 31; 43(6):3180-96. View in: PubMed

  16. Shinohara M, Hayashihara K, Grubb JT, Bishop DK, Shinohara A. DNA damage response clamp 9-1-1 promotes assembly of ZMM proteins for formation of crossovers and synaptonemal complex. J Cell Sci. 2015 Apr 15; 128(8):1494-506. View in: PubMed

  17. Wood S, Feng J, Chung J, Radojcic V, Sandy-Sloat AR, Friedman A, Shelton A, Yan M, Siebel CW, Bishop DK, Maillard I. Transient blockade of delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation. J Immunol. 2015 Mar 15; 194(6):2899-908. View in: PubMed

  18. Joshi N, Brown MS, Bishop DK, B?rner GV. Gradual implementation of the meiotic recombination program via checkpoint pathways controlled by global DSB levels. Mol Cell. 2015 Mar 05; 57(5):797-811. View in: PubMed

  19. Brown MS, Bishop DK. DNA strand exchange and RecA homologs in meiosis. Cold Spring Harb Perspect Biol. 2014 Dec 04; 7(1):a016659. View in: PubMed

  20. Chan YL, Brown MS, Qin D, Handa N, Bishop DK. The third exon of the budding yeast meiotic recombination gene HOP2 is required for calcium-dependent and recombinase Dmc1-specific stimulation of homologous strand assimilation. J Biol Chem. 2014 Jun 27; 289(26):18076-86. View in: PubMed

  21. Mason JM, Logan HL, Budke B, Wu M, Pawlowski M, Weichselbaum RR, Kozikowski AP, Bishop DK, Connell PP. The RAD51-stimulatory compound RS-1 can exploit the RAD51 overexpression that exists in cancer cells and tumors. Cancer Res. 2014 Jul 01; 74(13):3546-55. View in: PubMed

  22. Lao JP, Cloud V, Huang CC, Grubb J, Thacker D, Lee CY, Dresser ME, Hunter N, Bishop DK. Meiotic crossover control by concerted action of Rad51-Dmc1 in homolog template bias and robust homeostatic regulation. PLoS Genet. 2013; 9(12):e1003978. View in: PubMed

  23. Krill KT, Csencsits-Smith K, Wood SC, Faust S, Lu G, Bishop DK. Glucocorticoid-induced TNFR-related protein stimulation reverses cardiac allograft acceptance induced by CD40-CD40L blockade. Clin Dev Immunol. 2013; 2013:986859. View in: PubMed

  24. Budke B, Chan YL, Bishop DK, Connell PP. Real-time solution measurement of RAD51- and RecA-mediated strand assimilation without background annealing. Nucleic Acids Res. 2013 Jul; 41(13):e130. View in: PubMed

  25. Bishop DK. Rad51, the lead in mitotic recombinational DNA repair, plays a supporting role in budding yeast meiosis. Cell Cycle. 2012 Nov 15; 11(22):4105-6. View in: PubMed

  26. Cloud V, Chan YL, Grubb J, Budke B, Bishop DK. Rad51 is an accessory factor for Dmc1-mediated joint molecule formation during meiosis. Science. 2012 Sep 07; 337(6099):1222-5. View in: PubMed

  27. Budke B, Logan HL, Kalin JH, Zelivianskaia AS, Cameron McGuire W, Miller LL, Stark JM, Kozikowski AP, Bishop DK, Connell PP. RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res. 2012 Aug; 40(15):7347-57. View in: PubMed

  28. Xiao X, Gong W, Demirci G, Liu W, Spoerl S, Chu X, Bishop DK, Turka LA, Li XC. New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol. 2012 Jan 15; 188(2):892-901. View in: PubMed

  29. Booth AJ, Grabauskiene S, Wood SC, Lu G, Burrell BE, Bishop DK. IL-6 promotes cardiac graft rejection mediated by CD4+ cells. J Immunol. 2011 Dec 01; 187(11):5764-71. View in: PubMed

  30. Danilowicz C, Feinstein E, Conover A, Coljee VW, Vlassakis J, Chan YL, Bishop DK, Prentiss M. RecA homology search is promoted by mechanical stress along the scanned duplex DNA. Nucleic Acids Res. 2012 Feb; 40(4):1717-27. View in: PubMed

  31. Booth AJ, Wood SC, Cornett AM, Dreffs AA, Lu G, Muro AF, White ES, Bishop DK. Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis. J Pathol. 2012 Mar; 226(4):609-18. View in: PubMed

  32. Qing Y, Yamazoe M, Hirota K, Dejsuphong D, Sakai W, Yamamoto KN, Bishop DK, Wu X, Takeda S. The epistatic relationship between BRCA2 and the other RAD51 mediators in homologous recombination. PLoS Genet. 2011 Jul; 7(7):e1002148. View in: PubMed

  33. Shah PP, Zheng X, Epshtein A, Carey JN, Bishop DK, Klein HL. Swi2/Snf2-related translocases prevent accumulation of toxic Rad51 complexes during mitotic growth. Mol Cell. 2010 Sep 24; 39(6):862-72. View in: PubMed

  34. Faust SM, Lu G, Wood SC, Bishop DK. TGFbeta neutralization within cardiac allografts by decorin gene transfer attenuates chronic rejection. J Immunol. 2009 Dec 01; 183(11):7307-13. View in: PubMed

  35. Faust SM, Lu G, Marini BL, Zou W, Gordon D, Iwakura Y, Laouar Y, Bishop DK. Role of T cell TGFbeta signaling and IL-17 in allograft acceptance and fibrosis associated with chronic rejection. J Immunol. 2009 Dec 01; 183(11):7297-306. View in: PubMed

  36. Ferrari SR, Grubb J, Bishop DK. The Mei5-Sae3 protein complex mediates Dmc1 activity in Saccharomyces cerevisiae. J Biol Chem. 2009 May 01; 284(18):11766-70. View in: PubMed

  37. Burrell BE, Lu G, Li XC, Bishop DK. OX40 costimulation prevents allograft acceptance induced by CD40-CD40L blockade. J Immunol. 2009 Jan 01; 182(1):379-90. View in: PubMed

  38. Jayathilaka K, Sheridan SD, Bold TD, Bochenska K, Logan HL, Weichselbaum RR, Bishop DK, Connell PP. A chemical compound that stimulates the human homologous recombination protein RAD51. Proc Natl Acad Sci U S A. 2008 Oct 14; 105(41):15848-53. View in: PubMed

  39. Burrell BE, Csencsits K, Lu G, Grabauskiene S, Bishop DK. CD8+ Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice. J Immunol. 2008 Sep 15; 181(6):3906-14. View in: PubMed

  40. Sheridan SD, Yu X, Roth R, Heuser JE, Sehorn MG, Sung P, Egelman EH, Bishop DK. A comparative analysis of Dmc1 and Rad51 nucleoprotein filaments. Nucleic Acids Res. 2008 Jul; 36(12):4057-66. View in: PubMed

  41. Mungara AK, Brown DL, Bishop DK, Wood SY, Cederna PS. Anti-CD40L monoclonal antibody treatment induces long-term, tissue-specific, immunologic hyporesponsiveness to peripheral nerve allografts. J Reconstr Microsurg. 2008 Apr; 24(3):189-95. View in: PubMed

  42. Martin RW, Connell PP, Bishop DK. The Yin and Yang of treating BRCA-deficient tumors. Cell. 2008 Mar 21; 132(6):919-20. View in: PubMed

  43. Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J. Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde. Cancer Res. 2007 Dec 01; 67(23):11117-22. View in: PubMed

  44. Longerich S, Orelli BJ, Martin RW, Bishop DK, Storb U. Brca1 in immunoglobulin gene conversion and somatic hypermutation. DNA Repair (Amst). 2008 Feb 01; 7(2):253-66. View in: PubMed

  45. McMahill MS, Sham CW, Bishop DK. Synthesis-dependent strand annealing in meiosis. PLoS Biol. 2007 Nov 06; 5(11):e299. View in: PubMed

  46. Martin RW, Orelli BJ, Yamazoe M, Minn AJ, Takeda S, Bishop DK. RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. Cancer Res. 2007 Oct 15; 67(20):9658-65. View in: PubMed

  47. Bishop DK. Multiple mechanisms of meiotic recombination. Cell. 2006 Dec 15; 127(6):1095-7. View in: PubMed

  48. Collins JT, Shi J, Burrell BE, Bishop DK, Dunnick WA. Induced expression of murine gamma2a by CD40 ligation independently of IFN-gamma. J Immunol. 2006 Oct 15; 177(8):5414-9. View in: PubMed

  49. Holzen TM, Shah PP, Olivares HA, Bishop DK. Tid1/Rdh54 promotes dissociation of Dmc1 from nonrecombinogenic sites on meiotic chromatin. Genes Dev. 2006 Sep 15; 20(18):2593-604. View in: PubMed

  50. Sheridan S, Bishop DK. Red-Hed regulation: recombinase Rad51, though capable of playing the leading role, may be relegated to supporting Dmc1 in budding yeast meiosis. Genes Dev. 2006 Jul 01; 20(13):1685-91. View in: PubMed

  51. Brown DL, Bishop DK, Wood SY, Cederna PS. Short-term anti-CD40 ligand costimulatory blockade induces tolerance to peripheral nerve allografts, resulting in improved skeletal muscle function. Plast Reconstr Surg. 2006 Jun; 117(7):2250-8. View in: PubMed

  52. Nojima K, Hochegger H, Saberi A, Fukushima T, Kikuchi K, Yoshimura M, Orelli BJ, Bishop DK, Hirano S, Ohzeki M, Ishiai M, Yamamoto K, Takata M, Arakawa H, Buerstedde JM, Yamazoe M, Kawamoto T, Araki K, Takahashi JA, Hashimoto N, Takeda S, Sonoda E. Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res. 2005 Dec 15; 65(24):11704-11. View in: PubMed

  53. Lee MH, Chang YC, Hong EL, Grubb J, Chang CS, Bishop DK, Wang TF. Calcium ion promotes yeast Dmc1 activity via formation of long and fine helical filaments with single-stranded DNA. J Biol Chem. 2005 Dec 09; 280(49):40980-4. View in: PubMed

  54. Csencsits K, Wood SC, Lu G, Bishop DK. Transforming growth factor-beta1 gene transfer is associated with the development of regulatory cells. Am J Transplant. 2005 Oct; 5(10):2378-84. View in: PubMed

  55. Chen YK, Leng CH, Olivares H, Lee MH, Chang YC, Kung WM, Ti SC, Lo YH, Wang AH, Chang CS, Bishop DK, Hsueh YP, Wang TF. Heterodimeric complexes of Hop2 and Mnd1 function with Dmc1 to promote meiotic homolog juxtaposition and strand assimilation. Proc Natl Acad Sci U S A. 2004 Jul 20; 101(29):10572-7. View in: PubMed

  56. Nathan MJ, Mold JE, Wood SC, Csencsits K, Lu G, Eichwald EJ, Bishop DK. Requirement for donor and recipient CD40 expression in cardiac allograft rejection: induction of Th1 responses and influence of donor-derived dendritic cells. J Immunol. 2004 Jun 01; 172(11):6626-33. View in: PubMed

  57. Connell PP, Siddiqui N, Hoffman S, Kuang A, Khatipov EA, Weichselbaum RR, Bishop DK. A hot spot for RAD51C interactions revealed by a peptide that sensitizes cells to cisplatin. Cancer Res. 2004 May 01; 64(9):3002-5. View in: PubMed

  58. Bishop DK, Zickler D. Early decision; meiotic crossover interference prior to stable strand exchange and synapsis. Cell. 2004 Apr 02; 117(1):9-15. View in: PubMed

  59. Rua D, Holzen T, Glick BS, Kron SJ, Bishop DK. Monitoring changes in the subcellular location of proteins in S. cerevisiae. Methods Mol Biol. 2004; 241:299-311. View in: PubMed

  60. Russell TD, Yan Q, Fan G, Khalifah AP, Bishop DK, Brody SL, Walter MJ. IL-12 p40 homodimer-dependent macrophage chemotaxis and respiratory viral inflammation are mediated through IL-12 receptor beta 1. J Immunol. 2003 Dec 15; 171(12):6866-74. View in: PubMed

  61. Shinohara M, Sakai K, Shinohara A, Bishop DK. Crossover interference in Saccharomyces cerevisiae requires a TID1/RDH54- and DMC1-dependent pathway. Genetics. 2003 Apr; 163(4):1273-86. View in: PubMed

  62. Lu G, Bishop DK. Theoretical and technical considerations for gene transfer into vascularized cardiac transplants. Methods Mol Biol. 2003; 219:135-44. View in: PubMed

  63. Yin D, Dujovny N, Ma L, Varghese A, Shen J, Bishop DK, Chong AS. IFN-gamma production is specifically regulated by IL-10 in mice made tolerant with anti-CD40 ligand antibody and intact active bone. J Immunol. 2003 Jan 15; 170(2):853-60. View in: PubMed

  64. Nathan MJ, Yin D, Eichwald EJ, Bishop DK. The immunobiology of inductive anti-CD40L therapy in transplantation: allograft acceptance is not dependent upon the deletion of graft-reactive T cells. Am J Transplant. 2002 Apr; 2(4):323-32. View in: PubMed

  65. Orelli BJ, Bishop DK. BRCA2 and homologous recombination. Breast Cancer Res. 2001; 3(5):294-8. View in: PubMed

  66. Hong EL, Shinohara A, Bishop DK. Saccharomyces cerevisiae Dmc1 protein promotes renaturation of single-strand DNA (ssDNA) and assimilation of ssDNA into homologous super-coiled duplex DNA. J Biol Chem. 2001 Nov 09; 276(45):41906-12. View in: PubMed

  67. Orelli BJ, Logsdon JM, Bishop DK. Nine novel conserved motifs in BRCA1 identified by the chicken orthologue. Oncogene. 2001 07 19; 20(32):4433-8. View in: PubMed

  68. Gasior SL, Olivares H, Ear U, Hari DM, Weichselbaum R, Bishop DK. Assembly of RecA-like recombinases: distinct roles for mediator proteins in mitosis and meiosis. Proc Natl Acad Sci U S A. 2001 Jul 17; 98(15):8411-8. View in: PubMed

  69. Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem. 2000 Aug 04; 275(31):23899-903. View in: PubMed

  70. Bishop DK, Nikolski Y, Oshiro J, Chon J, Shinohara M, Chen X. High copy number suppression of the meiotic arrest caused by a dmc1 mutation: REC114 imposes an early recombination block and RAD54 promotes a DMC1-independent DSB repair pathway. Genes Cells. 1999 Aug; 4(8):425-44. View in: PubMed

  71. Grushcow JM, Holzen TM, Park KJ, Weinert T, Lichten M, Bishop DK. Saccharomyces cerevisiae checkpoint genes MEC1, RAD17 and RAD24 are required for normal meiotic recombination partner choice. Genetics. 1999 Oct; 153(2):607-20. View in: PubMed

  72. Bishop DK, Ear U, Bhattacharyya A, Calderone C, Beckett M, Weichselbaum RR, Shinohara A. Xrcc3 is required for assembly of Rad51 complexes in vivo. J Biol Chem. 1998 Aug 21; 273(34):21482-8. View in: PubMed

  73. Gasior SL, Wong AK, Kora Y, Shinohara A, Bishop DK. Rad52 associates with RPA and functions with rad55 and rad57 to assemble meiotic recombination complexes. Genes Dev. 1998 Jul 15; 12(14):2208-21. View in: PubMed

  74. Bishop DK. RecA homologs Dmc1 and Rad51 interact to form multiple nuclear complexes prior to meiotic chromosome synapsis. Cell. 1994 Dec 16; 79(6):1081-92. View in: PubMed