Skip to main content

Advertisement

SpringerLink
Log in

Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy

  • Multi-Author Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Many cancer chemotherapeutic agents form DNA interstrand crosslinks (ICLs), extremely cytotoxic lesions that form covalent bonds between two opposing DNA strands, blocking DNA replication and transcription. However, cellular responses triggered by ICLs can cause resistance in tumor cells, limiting the efficacy of such treatment. Here we discuss recent advances in our understanding of the mechanisms of ICL repair that cause this resistance. The recent development of strategies for the synthesis of site-specific ICLs greatly contributed to these insights. Key features of repair are similar for all ICLs, but there is increasing evidence that the specifics of lesion recognition and synthesis past ICLs by DNA polymerases are dependent upon the structure of ICLs. These new insights provide a basis for the improvement of antitumor therapy by targeting DNA repair pathways that lead to resistance to treatment with crosslinking agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ICL:

Interstrand crosslink

NM:

Nitrogen mustards

NER:

Nucleotide excision repair

CENU:

Chloro nitroso urea

MMC:

Mitomycin C

FA:

Fanconi anemia

HR:

Homologous recombination

TLS:

Translesion synthesis

References

  1. DeVita VT, Chu E (2008) A history of cancer chemotherapy. Cancer Res 68:8643–8653

    Article  PubMed  CAS  Google Scholar 

  2. Epstein RJ (1990) Drug-induced DNA damage and tumor chemosensitivity. J Clin Oncol 8:2062–2084

    PubMed  CAS  Google Scholar 

  3. Schärer OD (2005) DNA interstrand crosslinks: natural and drug-induced DNA adducts that induce unique cellular responses. Chembiochem 6:27–32

    Article  PubMed  CAS  Google Scholar 

  4. Noll DM, Mason TM, Miller PS (2006) Formation and repair of interstrand cross-links in DNA. Chem Rev 106:277–301

    Article  PubMed  CAS  Google Scholar 

  5. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8:193–204

    Article  PubMed  CAS  Google Scholar 

  6. Goodman L, Wintrobe M, Dameshek W, Goodman M, Gilman A (1946) Nitrogen mustard therapy—use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc 132:126–132

    CAS  Google Scholar 

  7. Kohn KW (1996) Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment—Fifteenth Bruce F. Cain Memorial Award lecture. Cancer Res 56:5533–5546

    PubMed  CAS  Google Scholar 

  8. Gilman A, Philips F (1946) The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides. Science 103:409–436

    Article  PubMed  CAS  Google Scholar 

  9. Geiduschek EP (1961) “Reversible” DNA. Proc Natl Acad Sci USA 47:950–955

    Article  PubMed  CAS  Google Scholar 

  10. Brookes P, Lawley PD (1961) The reaction of mono- and di-functional alkylating agents with nucleic acids. Biochem J 80:496–503

    PubMed  CAS  Google Scholar 

  11. Kohn KW, Spears CL, Doty P (1966) Inter-strand crosslinking of DNA by nitrogen mustard. J Mol Biol 19:266–288

    Article  PubMed  CAS  Google Scholar 

  12. Rajski SR, Williams RM (1998) DNA cross-linking agents as antitumor drugs. Chem Rev 98:2723–2796

    Article  PubMed  CAS  Google Scholar 

  13. Stone MP, Cho Y-J, Huang H, Kim H-Y, Kozekov ID, Kozekova A, Wang H, Minko IG, Lloyd RS, Harris TM, Rizzo CJ (2008) Interstrand DNA cross-links induced by alpha, beta-unsaturated aldehydes derived from lipid peroxidation and environmental sources. Accounts Chem Res 41:793–804

    Article  CAS  Google Scholar 

  14. Panasci L, Xu Z-Y, Bello V, Aloyz R (2002) The role of DNA repair in nitrogen mustard drug resistance. Anticancer Drugs 13:211–220

    Article  PubMed  CAS  Google Scholar 

  15. McHugh PJ, Spanswick VJ, Hartley JA (2001) Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol 2:483–490

    Article  PubMed  CAS  Google Scholar 

  16. Ojwang JO, Grueneberg DA, Loechler EL (1989) Synthesis of a duplex oligonucleotide containing a nitrogen mustard interstrand DNA–DNA cross-link. Cancer Res 49:6529–6537

    PubMed  CAS  Google Scholar 

  17. Rink S, Solomon M, Taylor M, Rajur S, McLaughlin L, Hopkins P (1993) Covalent Structure of a nitrogen mustard-induced DNA interstrand cross-link—an N7-to-N7 linkage of deoxyguanosine residues at the duplex sequence 5′-d(GNC). J Am Chem Soc 115:2551–2557

    Article  CAS  Google Scholar 

  18. Millard J, Raucher S, Hopkins P (1990) Mechlorethamine cross-links deoxyguanosine residues at 5′-GNC sequences in duplex DNA fragments. J Am Chem Soc 112:2459–2460

    Article  CAS  Google Scholar 

  19. Rink SM, Hopkins PB (1995) A mechlorethamine-induced DNA interstrand cross-link bends duplex DNA. Biochemistry 34:1439–1445

    Article  PubMed  CAS  Google Scholar 

  20. Guainazzi A, Campbell AJ, Angelov T, Simmerling C, Schärer OD (2010) Synthesis and molecular modeling of a nitrogen mustard DNA interstrand crosslink. Chem Eur J (in press)

  21. Kallama S, Hemminki K (1984) Alkylation of guanosine by phosphoramide mustard, chloromethine hydrochloride and chlorambucil. Acta Pharmacol Toxicol 54:214–220

    Article  CAS  Google Scholar 

  22. Kallama S, Hemminki K (1986) Stabilities of 7-alkylguanosines and 7-deoxyguanosines formed by phosphoramide mustard and nitrogen mustard. Chem Biol Interact 57:85–96

    Article  PubMed  CAS  Google Scholar 

  23. Fan Y, Gold B (1999) Sequence-specificity for DNA interstrand cross-linking by alpha, ω-alkanediol dimethylsulfonate esters: evidence for DNA distortion by the initial monofunctional lesion. J Am Chem Soc 121:11942–11946

    Article  CAS  Google Scholar 

  24. Mehta JR, Przybylski M, Ludlum DB (1980) Alkylation of guanosine and deoxyguanosine by phosphoramide mustard. Cancer Res 40:4183–4186

    PubMed  CAS  Google Scholar 

  25. Grueneberg D, Ojwang J, Benasutti M, Hartman S, Loechler E (1991) Construction of a human shuttle vector containing a single nitrogen mustard interstrand, DNA–DNA cross-link at a unique plasmid location. Cancer Res 51:2268–2272

    PubMed  CAS  Google Scholar 

  26. Berardini M, Mackay W, Loechler E (1997) Evidence for a recombination-independent pathway for the repair of DNA interstrand cross-links based on a site-specific study with nitrogen mustard. Biochemistry 36:3506–3513

    Article  PubMed  CAS  Google Scholar 

  27. Berardini M, Foster P, Loechler E (1999) DNA polymerase II (polB) is involved in a new DNA repair pathway for DNA interstrand cross-links in Escherichia coli. J Bacteriol 181:2878–2882

    PubMed  CAS  Google Scholar 

  28. Angelov T, Guainazzi A, Schärer OD (2009) Generation of DNA interstrand cross-links by post-synthetic reductive amination. Org Lett 11:661–664

    Article  PubMed  CAS  Google Scholar 

  29. Rosenberg B, VanCamp L, Trosko JE, Mansour VH (1969) Platinum compounds: a new class of potent antitumour agents. Nature 222:385–386

    Article  PubMed  CAS  Google Scholar 

  30. Rosenberg B, VanCamp L, Krigas T (1965) Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 205:698–699

    Article  PubMed  CAS  Google Scholar 

  31. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573–584

    Article  PubMed  CAS  Google Scholar 

  32. Jamieson ER, Lippard SJ (1999) Structure, recognition, and processing of cisplatin-DNA adducts. Chem Rev 99:2467–2498

    Article  PubMed  CAS  Google Scholar 

  33. Huang H, Zhu L, Reid BR, Drobny GP, Hopkins PB (1995) Solution structure of a cisplatin-induced DNA interstrand cross-link. Science 270:1842–1845

    Article  PubMed  CAS  Google Scholar 

  34. Coste F, Malinge JM, Serre L, Shepard W, Roth M, Leng M, Zelwer C (1999) Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 Å resolution: hydration at the platinated site. Nucleic Acids Res 27:1837–1846

    Article  PubMed  CAS  Google Scholar 

  35. Hofr C, Brabec V (2001) Thermal and thermodynamic properties of duplex DNA containing site-specific interstrand cross-link of antitumor cisplatin or its clinically ineffective trans isomer. J Biol Chem 276:9655–9661

    Article  PubMed  CAS  Google Scholar 

  36. Räschle M, Knipscheer P, Knipsheer P, Enoiu M, Angelov T, Sun J, Griffith JD, Ellenberger TE, Schärer OD, Walter JC (2008) Mechanism of replication-coupled DNA interstrand crosslink repair. Cell 134:969–980

    Article  PubMed  CAS  Google Scholar 

  37. Zhu G, Lippard SJ (2009) Photoaffinity labeling reveals nuclear proteins that uniquely recognize cisplatin-DNA interstrand cross-links. Biochemistry 48:4916–4925

    Article  PubMed  CAS  Google Scholar 

  38. Johannessen T-CA, Bjerkvig R, Tysnes BB (2008) DNA repair and cancer stem-like cells—potential partners in glioma drug resistance? Cancer Treat Rev 34:558–567

    Article  PubMed  CAS  Google Scholar 

  39. Ludlum DB (1997) The chloroethylnitrosoureas: sensitivity and resistance to cancer chemotherapy at the molecular level. Cancer Invest 15:588–598

    Article  PubMed  CAS  Google Scholar 

  40. Fischhaber PL, Gall AS, Duncan JA, Hopkins PB (1999) Direct demonstration in synthetic oligonucleotides that N, N′-bis(2-chloroethyl)-nitrosourea cross links N1 of deoxyguanosine to N3 of deoxycytidine on opposite strands of duplex DNA. Cancer Res 59:4363–4368

    PubMed  CAS  Google Scholar 

  41. Alzeer J, Schärer OD (2006) A modified thymine for the synthesis of site-specific thymine–guanine DNA interstrand crosslinks. Nucleic Acids Res 34:4458–4466

    Article  PubMed  CAS  Google Scholar 

  42. Noll DM, Noronha AM, Miller PS (2001) Synthesis and characterization of DNA duplexes containing an N(4)C-ethyl-N(4)C interstrand cross-link. J Am Chem Soc 123:3405–3411

    Article  PubMed  CAS  Google Scholar 

  43. Wilds CJ, Noronha AM, Robidoux S, Miller PS (2004) Mispair-aligned N3T-alkyl-N3T interstrand cross-linked DNA: synthesis and characterization of duplexes with interstrand cross-links of variable lengths. J Am Chem Soc 126:9257–9265

    Article  PubMed  CAS  Google Scholar 

  44. Wilds CJ, Xu F, Noronha AM (2008) Synthesis and characterization of DNA containing an N-1-2′-deoxyinosine-ethyl-N-3-thymidine interstrand cross-link: a structural mimic of the cross-link formed by 1, 3-bis-(2-chloroethyl)-1-nitrosourea. Chem Res Toxicol 21:686–695

    Article  PubMed  CAS  Google Scholar 

  45. Smeaton MB, Hlavin EM, McGregor Mason T, Noronha AM, Wilds CJ, Miller PS (2008) Distortion-dependent unhooking of interstrand cross-links in mammalian cell extracts. Biochemistry 47:9920–9930

    Article  PubMed  CAS  Google Scholar 

  46. Smeaton MB, Hlavin EM, Noronha AM, Murphy SP, Wilds CJ, Miller PS (2009) Effect of cross-link structure on DNA interstrand cross-link repair synthesis. Chem Res Toxicol 22:1285–1297

    Article  PubMed  CAS  Google Scholar 

  47. Hofheinz R-D, Beyer U, Al-Batran S-E, Hartmann JT (2008) Mitomycin C in the treatment of gastrointestinal tumours: recent data and perspectives. Onkologie 31:271–281

    Article  PubMed  CAS  Google Scholar 

  48. Tomasz M, Lipman R, Chowdary D, Pawlak J, Verdine GL, Nakanishi K (1987) Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA. Science 235:1204–1208

    Article  PubMed  CAS  Google Scholar 

  49. Tomasz M, Chowdary D, Lipman R, Shimotakahara S, Veiro D, Walker V, Verdine GL (1986) Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct. Proc Natl Acad Sci USA 83:6702–6706

    Article  PubMed  CAS  Google Scholar 

  50. Rink SM, Lipman R, Alley SC, Hopkins PB, Tomasz M (1996) Bending of DNA by the mitomycin C-induced, GpG intrastrand cross-link. Chem Res Toxicol 9:382–389

    Article  PubMed  CAS  Google Scholar 

  51. Norman D, Live D, Sastry M, Lipman R, Hingerty BE, Tomasz M, Broyde S, Patel DJ (1990) NMR and computational characterization of mitomycin cross-linked to adjacent deoxyguanosines in the minor groove of the d(T-A-C-G-T-A).d(T-A-C-G-T-A) duplex. Biochemistry 29:2861–2875

    Article  PubMed  CAS  Google Scholar 

  52. Warren AJ, Ihnat MA, Ogdon SE, Rowell EE, Hamilton JW (1998) Binding of nuclear proteins associated with mammalian DNA repair to the mitomycin C-DNA interstrand crosslink. Environ Mol Mutagen 31:70–81

    Article  PubMed  CAS  Google Scholar 

  53. Mustra DJ, Warren AJ, Hamilton JW (2001) Preferential binding of human full-length XPA and the minimal DNA binding domain (XPA-MF122) with the mitomycin C-DNA interstrand cross-link. Biochemistry 40:7158–7164

    Article  PubMed  CAS  Google Scholar 

  54. Zheng H, Wang X, Warren A, Legerski R, Nairn R, Hamilton J, Li L (2003) Nucleotide excision repair- and polymerase eta-mediated error-prone removal of mitomycin C interstrand cross-links. Mol Cell Biol 23:754–761

    Article  PubMed  CAS  Google Scholar 

  55. Cimino G, Gamper H, Isaacs S, Hearst J (1985) Psoralens as photoactive probes of nucleic acid structure and function: organic chemistry, photochemistry, and biochemistry. Annu Rev Biochem 54:1151–1193

    Article  PubMed  CAS  Google Scholar 

  56. Stern RS (2007) Psoralen and ultraviolet a light therapy for psoriasis. N Engl J Med 357:682–690

    Article  PubMed  CAS  Google Scholar 

  57. Spielmann HP, Sastry SS, Hearst JE (1992) Methods for the large-scale synthesis of psoralen furan-side monoadducts and diadducts. Proc Natl Acad Sci USA 89:4514–4518

    Article  PubMed  CAS  Google Scholar 

  58. Kobertz W, Essigmann JM (1997) Solid-phase synthesis of oligonucleotides containing a site-specific psoralen derivative. J Am Chem Soc 119:5960–5961

    Article  CAS  Google Scholar 

  59. Spielmann HP, Dwyer TJ, Hearst JE, Wemmer DE (1995) Solution structures of psoralen monoadducted and cross-linked DNA oligomers by NMR spectroscopy and restrained molecular dynamics. Biochemistry 34:12937–12953

    Article  PubMed  CAS  Google Scholar 

  60. Hwang GS, Kim JK, Choi BS (1996) The solution structure of a psoralen cross-linked DNA duplex by NMR and relaxation matrix refinement. Biochem Biophys Res Commun 219:191–197

    Article  PubMed  CAS  Google Scholar 

  61. Sinden RR, Hagerman PJ (1984) Interstrand psoralen cross-links do not introduce appreciable bends in DNA. Biochemistry 23:6299–6303

    Article  PubMed  CAS  Google Scholar 

  62. Thazhathveetil AK, Liu ST, Indig FE, Seidman MM (2007) Psoralen conjugates for visualization of genomic interstrand cross-links localized by laser photoactivation. Bioconjug Chem 18:431–437

    Article  PubMed  CAS  Google Scholar 

  63. Majumdar A, Muniandy PA, Liu J, Liu JL, Liu ST, Cuenoud B, Seidman MM (2008) Targeted gene knock in and sequence modulation mediated by a psoralen-linked triplex-forming oligonucleotide. J Biol Chem 283:11244–11252

    Article  PubMed  CAS  Google Scholar 

  64. Niedernhofer LJ, Daniels JS, Rouzer CA, Greene RE, Marnett LJ (2003) Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. J Biol Chem 278:31426–31433

    Article  PubMed  CAS  Google Scholar 

  65. Cheng G, Shi Y, Sturla SJ, Jalas JR, McIntee EJ, Villalta PW, Wang M, Hecht SS (2003) Reactions of formaldehyde plus acetaldehyde with deoxyguanosine and DNA: formation of cyclic deoxyguanosine adducts and formaldehyde cross-links. Chem Res Toxicol 16:145–152

    Article  PubMed  CAS  Google Scholar 

  66. Minko IG, Harbut MB, Kozekov ID, Kozekova A, Jakobs PM, Olson SB, Moses RE, Harris TM, Rizzo CJ, Lloyd RS (2008) Role for DNA polymerase kappa in the processing of N2-N2-guanine interstrand cross-links. J Biol Chem 283:17075–17082

    Article  PubMed  CAS  Google Scholar 

  67. Dooley PA, Tsarouhtsis D, Korbel GA, Nechev LV, Shearer J, Zegar IS, Harris CM, Stone MP, Harris TM (2001) Structural studies of an oligodeoxynucleotide containing a trimethylene interstrand cross-link in a 5′-(CpG) motif: model of a malondialdehyde cross-link. J Am Chem Soc 123:1730–1739

    Article  PubMed  CAS  Google Scholar 

  68. Dooley PA, Zhang M, Korbel GA, Nechev LV, Harris CM, Stone MP, Harris TM (2003) NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5′-d(GpC) motif. J Am Chem Soc 125:62–72

    Article  PubMed  CAS  Google Scholar 

  69. Shapiro R, Dubelman S, Feinberg AM, Crain PF, McCloskey JA (1977) Isolation and identification of cross-linked nucleosides from nitrous acid treated deoxyribonucleic acid. J Am Chem Soc 99:302–303

    Article  PubMed  CAS  Google Scholar 

  70. Kirchner J, Hopkins P (1991) Nitrous-acid cross-links duplex DNA fragments through deoxyguanosine residues at the sequence 5′-CG. J Am Chem Soc 113:4681–4682

    Article  CAS  Google Scholar 

  71. Caulfield JL, Wishnok JS, Tannenbaum SR (2003) Nitric oxide-induced interstrand cross-links in DNA. Chem Res Toxicol 16:571–574

    Article  PubMed  CAS  Google Scholar 

  72. Edfeldt NBF, Harwood EA, Sigurdsson ST, Hopkins PB, Reid BR (2004) Solution structure of a nitrous acid induced DNA interstrand cross-link. Nucleic Acids Res 32:2785–2794

    Article  PubMed  CAS  Google Scholar 

  73. Harwood E, Sigurdsson S, Edfeldt N, Reid B, Hopkins PB (1999) Chemical synthesis and preliminary structural characterization of a nitrous acid interstrand cross-linked duplex DNA. J Am Chem Soc 121:5081–5082

    Article  CAS  Google Scholar 

  74. Hong IS, Greenberg MM (2005) Efficient DNA interstrand cross-link formation from a nucleotide radical. J Am Chem Soc 127:3692–3693

    Article  PubMed  CAS  Google Scholar 

  75. Hong IS, Ding H, Greenberg MM (2006) Oxygen independent DNA interstrand cross-link formation by a nucleotide radical. J Am Chem Soc 128:485–491

    Article  PubMed  CAS  Google Scholar 

  76. Cole R (1973) Repair of DNA containing interstrand crosslinks in Escherichia coli: sequential excision and recombination. Proc Natl Acad Sci USA 70:1064–1068

    Article  PubMed  CAS  Google Scholar 

  77. Cole R, Levitan D, Sinden R (1976) Removal of psoralen interstrand cross-links from DNA of Escherichia coli: mechanism and genetic control. J Mol Biol 103:39–59

    Article  PubMed  CAS  Google Scholar 

  78. Akkari Y, Bateman R, Reifsteck C, Olson S, Grompe M (2000) DNA replication is required to elicit cellular responses to psoralen-induced DNA interstrand cross-links. Mol Cell Biol 20:8283–8289

    Article  PubMed  CAS  Google Scholar 

  79. Hoy CA, Thompson LH, Mooney CL, Salazar EP (1985) Defective DNA cross-link removal in Chinese hamster cell mutants hypersensitive to bifunctional alkylating agents. Cancer Res 45:1737–1743

    PubMed  CAS  Google Scholar 

  80. De Silva IU, McHugh PJ, Clingen PH, Hartley JA (2000) Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. Mol Cell Biol 20:7980–7990

    Article  PubMed  Google Scholar 

  81. Niedernhofer LJ, Odijk H, Budzowska M, van Drunen E, Maas A, Theil AF, de Wit J, Jaspers NGJ, Beverloo HB, Hoeijmakers JHJ, Kanaar R (2004) The structure-specific endonuclease Ercc1–Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Mol Cell Biol 24:5776–5787

    Article  PubMed  CAS  Google Scholar 

  82. Hanada K, Budzowska M, Modesti M, Maas A, Wyman C, Essers J, Kanaar R (2006) The structure-specific endonuclease Mus81–Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks. EMBO J 25:4921–4932

    Article  PubMed  CAS  Google Scholar 

  83. Hanada K, Budzowska M, Davies S, van Drunen E, Onizawa H, Beverloo HB, Maas A, Essers J, Hickson I, Kanaar R (2007) The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nat Struct Mol Biol 14:1096–1104

    Article  PubMed  CAS  Google Scholar 

  84. Simpson LJ, Sale JE (2003) Rev1 is essential for DNA damage tolerance and non-templated immunoglobulin gene mutation in a vertebrate cell line. EMBO J 22:1654–1664

    Article  PubMed  CAS  Google Scholar 

  85. Niedzwiedz W, Mosedale G, Johnson M, Ong C, Pace P, Patel KJ (2004) The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol Cell 15:607–620

    Article  PubMed  CAS  Google Scholar 

  86. Gan GN, Wittschieben JP, Wittschieben BØ, Wood RD (2008) DNA polymerase zeta (pol zeta) in higher eukaryotes. Cell Res 18:174–183

    Article  PubMed  CAS  Google Scholar 

  87. Essers J, Hendriks RW, Swagemakers SM, Troelstra C, de Wit J, Bootsma D, Hoeijmakers JH, Kanaar R (1997) Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell 89:195–204

    Article  PubMed  CAS  Google Scholar 

  88. Liu N, Lamerdin JE, Tebbs RS, Schild D, Tucker JD, Shen MR, Brookman KW, Siciliano MJ, Walter CA, Fan W, Narayana LS, Zhou ZQ, Adamson AW, Sorensen KJ, Chen DJ, Jones NJ, Thompson LH (1998) XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages. Mol Cell 1:783–793

    Article  PubMed  CAS  Google Scholar 

  89. Niedernhofer LJ, Lalai AS, Hoeijmakers JHJ (2005) Fanconi anemia (cross)linked to DNA repair. Cell 123:1191–1198

    Article  PubMed  CAS  Google Scholar 

  90. Wang W (2007) Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8:735–748

    Article  PubMed  CAS  Google Scholar 

  91. Moldovan G-L, D’Andrea AD (2009) How the Fanconi anemia pathway guards the genome. Annu Rev Genet 43:223–249

    Article  PubMed  CAS  Google Scholar 

  92. Walter J, Sun L, Newport J (1998) Regulated chromosomal DNA replication in the absence of a nucleus. Mol Cell 1:519–529

    Article  PubMed  CAS  Google Scholar 

  93. Yan Z, Delannoy M, Ling C, Daee D, Osman F, Muniandy PA, Shen X, Oostra AB, Du H, Steltenpool J, Lin T, Schuster B, Décaillet C, Stasiak A, Stasiak AZ, Stone S, Hoatlin ME, Schindler D, Woodcock CL, Joenje H, Sen R, de Winter JP, Li L, Seidman MM, Whitby MC, Myung K, Constantinou A, Wang W (2010) A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol Cell 37:865–878

    Article  PubMed  CAS  Google Scholar 

  94. Singh TR, Saro D, Ali AM, Zheng X-F, Du C-h, Killen MW, Sachpatzidis A, Wahengbam K, Pierce AJ, Xiong Y, Sung P, Meetei AR (2010) MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Mol Cell 37:879–886

    Article  PubMed  CAS  Google Scholar 

  95. Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W (2005) A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet 37:958–963

    Article  PubMed  CAS  Google Scholar 

  96. Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR, Laghmani EH, Joenje H, McDonald N, de Winter JP, Wang W, West SC (2007) Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol Cell 25:331–343

    Article  PubMed  CAS  Google Scholar 

  97. Collis SJ, Ciccia A, Deans AJ, Horejsí Z, Martin JS, Maslen SL, Skehel JM, Elledge SJ, West SC, Boulton SJ (2008) FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol Cell 32:313–324

    Article  PubMed  CAS  Google Scholar 

  98. Meetei A, de Winter JP, Medhurst A, Wallisch M, Waisfisz Q, van de Vrugt H, Oostra A, Yan Z, Ling C, Bishop C, Hoatlin M, Joenje H, Wang W (2003) A novel ubiquitin ligase is deficient in Fanconi anemia. Nat Genet 35:165–170

    Article  PubMed  CAS  Google Scholar 

  99. Cole AR, Lewis LPC, Walden H (2010) The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nat Struct Mol Biol 17:294–298

    Article  PubMed  CAS  Google Scholar 

  100. Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn M, Timmers C, Hejna J, Grompe M, D’Andrea AD (2001) Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 7:249–262

    Article  PubMed  CAS  Google Scholar 

  101. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald E, Hurov K, Luo J, Ballif B, Gygi S, Hofmann K, D’Andrea AD, Elledge S (2007) Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129:289–301

    Article  PubMed  CAS  Google Scholar 

  102. Knipscheer P, Räschle M, Smogorzewska A, Enoiu M, Ho TV, Schärer OD, Walter JC, Elledge SJ (2009) The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science 326:1698–1701

    Article  PubMed  CAS  Google Scholar 

  103. Ben-Yehoyada M, Wang LC, Kozekov ID, Rizzo CJ, Gottesman ME, Gautier J (2009) Checkpoint signaling from a single DNA interstrand crosslink. Mol Cell 35:704–715

    Article  PubMed  CAS  Google Scholar 

  104. Shen X, Do H, Li Y, Chung W-H, Tomasz M, de Winter JP, Xia B, Elledge SJ, Wang W, Li L (2009) Recruitment of Fanconi anemia and breast cancer proteins to DNA damage sites is differentially governed by replication. Mol Cell 35:716–723

    Article  PubMed  CAS  Google Scholar 

  105. McHugh P, Sones W, Hartley J (2000) Repair of intermediate structures produced at DNA interstrand cross-links in Saccharomyces cerevisiae. Mol Cell Biol 20:3425–3433

    Article  PubMed  CAS  Google Scholar 

  106. Dendouga N, Gao H, Moechars D, Janicot M, Vialard J, McGowan CH (2005) Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis. Mol Cell Biol 25:7569–7579

    Article  PubMed  CAS  Google Scholar 

  107. Ciccia A, McDonald N, West S (2008) Structural and functional relationships of the XPF/MUS81 family of proteins. Annu Rev Biochem 77:259–287

    Article  PubMed  CAS  Google Scholar 

  108. Rothfuss A, Grompe M (2004) Repair kinetics of genomic interstrand DNA cross-links: evidence for DNA double-strand break-dependent activation of the Fanconi anemia/BRCA pathway. Mol Cell Biol 24:123–134

    Article  PubMed  CAS  Google Scholar 

  109. Bhagwat N, Olsen AL, Wang AT, Hanada K, Stuckert P, Kanaar R, D’Andrea A, Niedernhofer LJ, McHugh PJ (2009) XPF-ERCC1 participates in the Fanconi anemia pathway of cross-link repair. Mol Cell Biol 29:6427–6437

    Article  PubMed  CAS  Google Scholar 

  110. McCabe KM, Hemphill A, Akkari Y, Jakobs PM, Pauw D, Olson SB, Moses RE, Grompe M (2008) ERCC1 is required for FANCD2 focus formation. Mol Genet Metab 95:66–73

    Article  PubMed  CAS  Google Scholar 

  111. Bergstralh DT, Sekelsky J (2008) Interstrand crosslink repair: can XPF-ERCC1 be let off the hook? Trends Genet 24:70–76

    Article  PubMed  CAS  Google Scholar 

  112. Fekairi S, Scaglione S, Chahwan C, Taylor ER, Tissier A, Coulon S, Dong M-Q, Ruse C, Yates JR, Russell P, Fuchs RP, McGowan CH, Gaillard P-HL (2009) Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell 138:78–89

    Article  PubMed  CAS  Google Scholar 

  113. Svendsen JM, Smogorzewska A, Sowa ME, O’Connell BC, Gygi SP, Elledge SJ, Harper JW (2009) Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 138:63–77

    Article  PubMed  CAS  Google Scholar 

  114. Muñoz IM, Hain K, Déclais A-C, Gardiner M, Toh GW, Sanchez-Pulido L, Heuckmann JM, Toth R, Macartney T, Eppink B, Kanaar R, Ponting CP, Lilley DMJ, Rouse J (2009) Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol Cell 35:116–127

    Article  PubMed  CAS  Google Scholar 

  115. Andersen SL, Bergstralh DT, Kohl KP, LaRocque JR, Moore CB, Sekelsky J (2009) Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structure-specific endonucleases in DNA repair and recombination. Mol Cell 35:128–135

    Article  PubMed  CAS  Google Scholar 

  116. Loeb LA, Monnat RJ (2008) DNA polymerases and human disease. Nat Rev Genet 9:594–604

    Article  PubMed  CAS  Google Scholar 

  117. Yang W, Woodgate R (2007) What a difference a decade makes: insights into translesion DNA synthesis. Proc Natl Acad Sci USA 104:15591–15598

    Article  PubMed  Google Scholar 

  118. Prakash S, Johnson RE, Prakash L (2005) Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu Rev Biochem 74:317–353

    Article  PubMed  CAS  Google Scholar 

  119. Yamanaka K, Minko IG, Takata K-I, Kolbanovskiy A, Kozekov ID, Wood RD, Rizzo CJ, Lloyd RS (2010) Novel enzymatic function of DNA polymerase nu in translesion DNA synthesis past major groove DNA–peptide and DNA–DNA cross-links. Chem Res Toxicol 23:689–695

    Article  PubMed  CAS  Google Scholar 

  120. Hinz JM (2010) Role of homologous recombination in DNA interstrand crosslink repair. Environ Mol Mutagen 51:582–603

    Google Scholar 

  121. Muniandy PA, Liu J, Majumdar A, Liu S-t, Seidman MM (2010) DNA interstrand crosslink repair in mammalian cells: step by step. Crit Rev Biochem Mol Biol 45:23–49

    Article  PubMed  CAS  Google Scholar 

  122. Sarkar S, Davies AA, Ulrich HD, McHugh PJ (2006) DNA interstrand crosslink repair during G1 involves nucleotide excision repair and DNA polymerase zeta. EMBO J 25:1285–1294

    Article  PubMed  CAS  Google Scholar 

  123. Wang X, Peterson C, Zheng H, Nairn R, Legerski R, Li L (2001) Involvement of nucleotide excision repair in a recombination-independent and error-prone pathway of DNA interstrand cross-link repair. Mol Cell Biol 21:713–720

    Article  PubMed  CAS  Google Scholar 

  124. Shen X, Jun S, O’Neal LE, Sonoda E, Bemark M, Sale J, Li L (2006) REV3 and REV1 play major roles in recombination-independent repair of DNA interstrand cross-links mediated by monoubiquitinated proliferating cell nuclear antigen (PCNA). J Biol Chem 281:13869–13872

    Article  PubMed  CAS  Google Scholar 

  125. Hlavin EM, Smeaton MB, Miller PS (2010) Initiation of DNA interstrand cross-link repair in mammalian cells. Environ Mol Mutagen 51:604–624

    Google Scholar 

  126. Nojima K, Hochegger H, Saberi A, Fukushima T, Kikuchi K, Yoshimura M, Orelli B, Bishop D, Hirano S, Ohzeki M, Ishiai M, Yamamoto K, Takata M, Arakawa H, Buerstedde J, Yamazoe M, Kawamoto T, Araki K, Takahashi J, Hashimoto N, Takeda S, Sonoda E (2005) Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res 65:11704–11711

    Article  PubMed  CAS  Google Scholar 

  127. Gillet LCJ, Schärer OD (2006) Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem Rev 106:253–276

    Article  PubMed  CAS  Google Scholar 

  128. Hanawalt P, Spivak G (2008) Transcription-coupled DNA repair: two decades of progress and surprises. Nat Rev Mol Cell Biol 9:958–970

    Article  PubMed  CAS  Google Scholar 

  129. Muniandy PA, Thapa D, Thazhathveetil AK, Liu S-t, Seidman MM (2009) Repair of laser-localized DNA interstrand cross-links in G1 phase mammalian cells. J Biol Chem 284:27908–27917

    Article  PubMed  CAS  Google Scholar 

  130. Zamble DB, Mu D, Reardon JT, Sancar A, Lippard SJ (1996) Repair of cisplatin—DNA adducts by the mammalian excision nuclease. Biochemistry 35:10004–10013

    Article  PubMed  CAS  Google Scholar 

  131. Min J-H, Pavletich NP (2007) Recognition of DNA damage by the Rad4 nucleotide excision repair protein. Nature 449:570–575

    Article  PubMed  CAS  Google Scholar 

  132. Schärer OD (2007) Achieving broad substrate specificity in damage recognition by binding accessible nondamaged DNA. Mol Cell 28:184–186

    Article  PubMed  CAS  Google Scholar 

  133. Maillard O, Camenisch U, Blagoev KB, Naegeli H (2008) Versatile protection from mutagenic DNA lesions conferred by bipartite recognition in nucleotide excision repair. Mutat Res 658:271–286

    Article  PubMed  CAS  Google Scholar 

  134. Zhao J, Jain A, Iyer RR, Modrich PL, Vasquez KM (2009) Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks. Nucleic Acids Res 37:4420–4429

    Article  PubMed  CAS  Google Scholar 

  135. Zhang Y, Wu X, Guo D, Rechkoblit O, Geacintov NE, Wang Z (2002) Two-step error-prone bypass of the (+)- and (−)-trans-anti-BPDE-N2-dG adducts by human DNA polymerases eta and kappa. Mutat Res 510:23–35

    PubMed  CAS  Google Scholar 

  136. Bessho T, Mu D, Sancar A (1997) Initiation of DNA interstrand cross-link repair in humans: the nucleotide excision repair system makes dual incisions 5′ to the cross-linked base and removes a 22- to 28-nucleotide-long damage-free strand. Mol Cell Biol 17:6822–6830

    PubMed  CAS  Google Scholar 

  137. Mu D, Bessho T, Nechev LV, Chen DJ, Harris TM, Hearst JE, Sancar A (2000) DNA interstrand cross-links induce futile repair synthesis in mammalian cell extracts. Mol Cell Biol 20:2446–2454

    Article  PubMed  CAS  Google Scholar 

  138. Martin LP, Hamilton TC, Schilder RJ (2008) Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14:1291–1295

    Article  PubMed  CAS  Google Scholar 

  139. Spanswick VJ, Hartley JM, Hartley JA (2010) Measurement of DNA interstrand crosslinking in individual cells using the single cell gel electrophoresis (Comet) assay. Methods Mol Biol 613:267–282

    Article  PubMed  CAS  Google Scholar 

  140. Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NMB, Jackson SP, Smith GCM, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  PubMed  CAS  Google Scholar 

  141. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917

    Article  PubMed  CAS  Google Scholar 

  142. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JHM, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134

    Article  PubMed  CAS  Google Scholar 

  143. Gallmeier E, Calhoun ES, Rago C, Brody JR, Cunningham SC, Hucl T, Gorospe M, Kohli M, Lengauer C, Kern SE (2006) Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options. Gastroenterology 130:2145–2154

    Article  PubMed  CAS  Google Scholar 

  144. Gallmeier E, Kern SE (2007) Targeting Fanconi anemia/BRCA2 pathway defects in cancer: the significance of preclinical pharmacogenomic models. Clin Cancer Res 13:4–10

    Article  PubMed  CAS  Google Scholar 

  145. Chirnomas D, Taniguchi T, de la Vega M, Vaidya AP, Vasserman M, Hartman A-R, Kennedy R, Foster R, Mahoney J, Seiden MV, D’Andrea AD (2006) Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol Cancer Ther 5:952–961

    Article  PubMed  CAS  Google Scholar 

  146. Landais I, Sobeck A, Stone S, LaChapelle A, Hoatlin ME (2009) A novel cell-free screen identifies a potent inhibitor of the Fanconi anemia pathway. Int J Cancer 124:783–792

    Article  PubMed  CAS  Google Scholar 

  147. Kowal P, Gurtan AM, Stuckert P, D’Andrea AD, Ellenberger T (2007) Structural determinants of human FANCF protein that function in the assembly of a DNA damage signaling complex. J Biol Chem 282:2047–2055

    Article  PubMed  CAS  Google Scholar 

  148. Orelli B, McClendon TB, Tsodikov OV, Ellenberger TE, Niedernhofer LJ, Schärer OD (2010) The XPA-binding domain of ERCC1 is required for nucleotide excision repair but not other DNA repair pathways. J Biol Chem 285:3705–3712

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Suse Broyde (NYU) for providing the coordinates for the mitomycin C ICL. Work in the authors’ laboratory was supported by NIH grants GM080454, CA092584, and ES004068.

Author information

Authors and Affiliations

  1. Departments of Pharmacological Sciences, Chemistry 619, Stony Brook University, Stony Brook, NY, 11794-3400, USA

    Angelo Guainazzi

  2. Departments of Pharmacological Sciences and Chemistry, Chemistry 619, Stony Brook University, Stony Brook, NY, 11794-3400, USA

    Orlando D. Schärer

Authors
  1. Angelo Guainazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Orlando D. Schärer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Orlando D. Schärer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guainazzi, A., Schärer, O.D. Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy. Cell. Mol. Life Sci. 67, 3683–3697 (2010). https://doi.org/10.1007/s00018-010-0492-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0492-6

Keywords

Search

Navigation