DNA Double-strand Breaks with 5' Adducts Are Efficiently Channeled to the DNA2-mediated Resection Pathway

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2015 Oct 1

PMID 26420828

Citations 9

Authors

Margaret Tammaro

Shuren Liao

Neil Beeharry

Hong Yan

Affiliations

Soon will be listed here.

Abstract

DNA double-strand breaks (DSBs) with 5' adducts are frequently formed from many nucleic acid processing enzymes, in particular DNA topoisomerase 2 (TOP2). The key intermediate of TOP2 catalysis is the covalent complex (TOP2cc), consisting of two TOP2 subunits covalently linked to the 5' ends of the nicked DNA. In cells, TOP2ccs can be trapped by cancer drugs such as etoposide and then converted into DNA double-strand breaks (DSBs) that carry adducts at the 5' end. The repair of such DSBs is critical to the survival of cells, but the underlying mechanism is still not well understood. We found that etoposide-induced DSBs are efficiently resected into 3' single-stranded DNA in cells and the major nuclease for resection is the DNA2 protein. DNA substrates carrying model 5' adducts were efficiently resected in Xenopus egg extracts and immunodepletion of Xenopus DNA2 also strongly inhibited resection. These results suggest that DNA2-mediated resection is a major mechanism for the repair of DSBs with 5' adducts.

Citing Articles

Association Mapping of Drought Tolerance Indices in Ethiopian Durum Wheat ( ssp. durum).

Negisho K, Shibru S, Matros A, Pillen K, Ordon F, Wehner G Front Plant Sci. 2022; 13:838088.

PMID: 35693182 PMC: 9178276. DOI: 10.3389/fpls.2022.838088.

A DNA nick at Ku-blocked double-strand break ends serves as an entry site for exonuclease 1 (Exo1) or Sgs1-Dna2 in long-range DNA end resection.

Wang W, Daley J, Kwon Y, Xue X, Krasner D, Miller A J Biol Chem. 2018; 293(44):17061-17069.

PMID: 30224356 PMC: 6222114. DOI: 10.1074/jbc.RA118.004769.

Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes.

Lee K, Swan R, Sondka Z, Padget K, Cowell I, Austin C Int J Mol Sci. 2018; 19(7).

PMID: 30011940 PMC: 6073685. DOI: 10.3390/ijms19072056.

Dna2 initiates resection at clean DNA double-strand breaks.

Paudyal S, Li S, Yan H, Hunter T, You Z Nucleic Acids Res. 2017; 45(20):11766-11781.

PMID: 28981724 PMC: 5714177. DOI: 10.1093/nar/gkx830.

DNA2-An Important Player in DNA Damage Response or Just Another DNA Maintenance Protein?.

Pawlowska E, Szczepanska J, Blasiak J Int J Mol Sci. 2017; 18(7).

PMID: 28718810 PMC: 5536050. DOI: 10.3390/ijms18071562.

References

Nussenzweig A, Nussenzweig M . Origin of chromosomal translocations in lymphoid cancer. Cell. 2010; 141(1):27-38. PMC: 2874895. DOI: 10.1016/j.cell.2010.03.016. View

Bromberg K, Burgin A, Osheroff N . A two-drug model for etoposide action against human topoisomerase IIalpha. J Biol Chem. 2002; 278(9):7406-12. DOI: 10.1074/jbc.M212056200. View

Zeng Z, Cortes-Ledesma F, El Khamisy S, Caldecott K . TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. J Biol Chem. 2010; 286(1):403-9. PMC: 3012998. DOI: 10.1074/jbc.M110.181016. View

Yan H, Toczylowski T, McCane J, Chen C, Liao S . Replication protein A promotes 5'-->3' end processing during homology-dependent DNA double-strand break repair. J Cell Biol. 2011; 192(2):251-61. PMC: 3172182. DOI: 10.1083/jcb.201005110. View

Liao S, Toczylowski T, Yan H . Mechanistic analysis of Xenopus EXO1's function in 5'-strand resection at DNA double-strand breaks. Nucleic Acids Res. 2011; 39(14):5967-77. PMC: 3152354. DOI: 10.1093/nar/gkr216. View

Symington L, Gautier J . Double-strand break end resection and repair pathway choice. Annu Rev Genet. 2011; 45:247-71. DOI: 10.1146/annurev-genet-110410-132435. View

Pastink A, Eeken J, Lohman P . Genomic integrity and the repair of double-strand DNA breaks. Mutat Res. 2001; 480-481:37-50. DOI: 10.1016/s0027-5107(01)00167-1. View

Xiao H, Mao Y, Desai S, Zhou N, Ting C, Hwang J . The topoisomerase IIbeta circular clamp arrests transcription and signals a 26S proteasome pathway. Proc Natl Acad Sci U S A. 2003; 100(6):3239-44. PMC: 152276. DOI: 10.1073/pnas.0736401100. View

Kao G, McKenna W, Guenther M, Muschel R, Lazar M, Yen T . Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response. J Cell Biol. 2003; 160(7):1017-27. PMC: 2172769. DOI: 10.1083/jcb.200209065. View

10.

Vilenchik M, Knudson A . Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003; 100(22):12871-6. PMC: 240711. DOI: 10.1073/pnas.2135498100. View

11.

Challberg M, Ostrove J, Kelly Jr T . Initiation of adenovirus DNA replication: detection of covalent complexes between nucleotide and the 80-kilodalton terminal protein. J Virol. 1982; 41(1):265-70. PMC: 256748. DOI: 10.1128/JVI.41.1.265-270.1982. View

12.

Smythe C, Newport J . Systems for the study of nuclear assembly, DNA replication, and nuclear breakdown in Xenopus laevis egg extracts. Methods Cell Biol. 1991; 35:449-68. DOI: 10.1016/s0091-679x(08)60583-x. View

13.

Roca J, Ishida R, Berger J, Andoh T, Wang J . Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp. Proc Natl Acad Sci U S A. 1994; 91(5):1781-5. PMC: 43247. DOI: 10.1073/pnas.91.5.1781. View

14.

Keeney S, Giroux C, Kleckner N . Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell. 1997; 88(3):375-84. DOI: 10.1016/s0092-8674(00)81876-0. View

15.

Tennyson R, Lindsley J . Type II DNA topoisomerase from Saccharomyces cerevisiae is a stable dimer. Biochemistry. 1997; 36(20):6107-14. DOI: 10.1021/bi970152f. View

16.

Baumann P, West S . Role of the human RAD51 protein in homologous recombination and double-stranded-break repair. Trends Biochem Sci. 1998; 23(7):247-51. DOI: 10.1016/s0968-0004(98)01232-8. View

17.

ODriscoll M, Jeggo P . The role of double-strand break repair - insights from human genetics. Nat Rev Genet. 2005; 7(1):45-54. DOI: 10.1038/nrg1746. View

18.

Jazayeri A, Falck J, Lukas C, Bartek J, Smith G, Lukas J . ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol. 2005; 8(1):37-45. DOI: 10.1038/ncb1337. View

19.

Toczylowski T, Yan H . Mechanistic analysis of a DNA end processing pathway mediated by the Xenopus Werner syndrome protein. J Biol Chem. 2006; 281(44):33198-205. DOI: 10.1074/jbc.M605044200. View

20.

Sartori A, Lukas C, Coates J, Mistrik M, Fu S, Bartek J . Human CtIP promotes DNA end resection. Nature. 2007; 450(7169):509-14. PMC: 2409435. DOI: 10.1038/nature06337. View