FEN1 Functions in Long Patch Base Excision Repair Under Conditions of Oxidative Stress in Vertebrate Cells

Overview

Journal Mol Cancer Res

Specialty Cell Biology

Date 2010 Feb 11

PMID 20145043

Citations 24

Authors

Kenjiro Asagoshi

Keizo Tano

Paul D Chastain 2nd

Noritaka Adachi

Eiichiro Sonoda

Koji Kikuchi

Hideki Koyama

Kenji Nagata

David G Kaufman

Shunichi Takeda

Samuel H Wilson

Masami Watanabe

James A Swenberg

Jun Nakamura

Affiliations

Soon will be listed here.

Abstract

From in vitro studies, flap endonuclease 1 (FEN1) has been proposed to play a role in the long patch (LP) base excision repair (BER) subpathway. Yet the role of FEN1 in BER in the context of the living vertebrate cell has not been thoroughly explored. In the present study, we cloned a DT40 chicken cell line with a deletion in the FEN1 gene and found that these FEN1-deficient cells exhibited hypersensitivity to H(2)O(2). This oxidant produces genotoxic lesions that are repaired by BER, suggesting that the cells have a deficiency in BER affecting survival. In experiments with extracts from the isogenic FEN1 null and wild-type cell lines, the LP-BER activity of FEN1 null cells was deficient, whereas repair by the single-nucleotide BER subpathway was normal. Other consequences of the FEN1 deficiency were also evaluated. These results illustrate that FEN1 plays a role in LP-BER in higher eukaryotes, presumably by processing the flap-containing intermediates of BER.

Citing Articles

How Do ROS Induce NETosis? Oxidative DNA Damage, DNA Repair, and Chromatin Decondensation.

Azzouz D, Palaniyar N Biomolecules. 2024; 14(10).

PMID: 39456240 PMC: 11505619. DOI: 10.3390/biom14101307.

Human CST Stimulates Base Excision Repair to Prevent the Accumulation of Oxidative DNA Damage.

Wysong B, Schuck P, Sridharan M, Carrison S, Murakami Y, Balakrishnan L J Mol Biol. 2024; 436(16):168672.

PMID: 38908783 PMC: 11864811. DOI: 10.1016/j.jmb.2024.168672.

The type of DNA damage response after decitabine treatment depends on the level of DNMT activity.

Aumer T, Dather M, Bergmayr L, Kartika S, Zeng T, Ge Q Life Sci Alliance. 2024; 7(9).

PMID: 38906675 PMC: 11192838. DOI: 10.26508/lsa.202302437.

Decline of DNA damage response along with myogenic differentiation.

Sutcu H, Rassinoux P, Donnio L, Neuillet D, Vianna F, Gabillot O Life Sci Alliance. 2023; 7(2).

PMID: 37993260 PMC: 10665522. DOI: 10.26508/lsa.202302279.

RNA G-Quadruplex within the 5'-UTR of FEN1 Regulates mRNA Stability under Oxidative Stress.

Ma Y, Yang Y, Xin J, He L, Hu Z, Gao T Antioxidants (Basel). 2023; 12(2).

PMID: 36829835 PMC: 9952066. DOI: 10.3390/antiox12020276.

References

Meira L, Burgis N, Samson L . Base excision repair. Adv Exp Med Biol. 2008; 570:125-73. DOI: 10.1007/1-4020-3764-3_5. View

Jin Y, Obert R, Burgers P, Kunkel T, Resnick M, Gordenin D . The 3'-->5' exonuclease of DNA polymerase delta can substitute for the 5' flap endonuclease Rad27/Fen1 in processing Okazaki fragments and preventing genome instability. Proc Natl Acad Sci U S A. 2001; 98(9):5122-7. PMC: 33174. DOI: 10.1073/pnas.091095198. View

Sobol R, Prasad R, Evenski A, Baker A, Yang X, Horton J . The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity. Nature. 2000; 405(6788):807-10. DOI: 10.1038/35015598. View

Braithwaite E, Kedar P, Lan L, Polosina Y, Asagoshi K, Poltoratsky V . DNA polymerase lambda protects mouse fibroblasts against oxidative DNA damage and is recruited to sites of DNA damage/repair. J Biol Chem. 2005; 280(36):31641-7. DOI: 10.1074/jbc.C500256200. View

Jin Y, Ayyagari R, Resnick M, Gordenin D, Burgers P . Okazaki fragment maturation in yeast. II. Cooperation between the polymerase and 3'-5'-exonuclease activities of Pol delta in the creation of a ligatable nick. J Biol Chem. 2002; 278(3):1626-33. DOI: 10.1074/jbc.M209803200. View

Harrigan J, Wilson 3rd D, Prasad R, Opresko P, Beck G, May A . The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta. Nucleic Acids Res. 2006; 34(2):745-54. PMC: 1356534. DOI: 10.1093/nar/gkj475. View

Piersen C, Prasad R, Wilson S, Lloyd R . Evidence for an imino intermediate in the DNA polymerase beta deoxyribose phosphate excision reaction. J Biol Chem. 1996; 271(30):17811-5. DOI: 10.1074/jbc.271.30.17811. View

Demott M, Beyret E, Wong D, Bales B, Hwang J, Greenberg M . Covalent trapping of human DNA polymerase beta by the oxidative DNA lesion 2-deoxyribonolactone. J Biol Chem. 2002; 277(10):7637-40. DOI: 10.1074/jbc.C100577200. View

Dorn E, Chastain 2nd P, Hall J, Cook J . Analysis of re-replication from deregulated origin licensing by DNA fiber spreading. Nucleic Acids Res. 2008; 37(1):60-9. PMC: 2615611. DOI: 10.1093/nar/gkn912. View

10.

Prakash S, Sung P, Prakash L . DNA repair genes and proteins of Saccharomyces cerevisiae. Annu Rev Genet. 1993; 27:33-70. DOI: 10.1146/annurev.ge.27.120193.000341. View

11.

Sobol R, Horton J, Kuhn R, Gu H, Singhal R, Prasad R . Requirement of mammalian DNA polymerase-beta in base-excision repair. Nature. 1996; 379(6561):183-6. DOI: 10.1038/379183a0. View

12.

Singhal R, Prasad R, Wilson S . DNA polymerase beta conducts the gap-filling step in uracil-initiated base excision repair in a bovine testis nuclear extract. J Biol Chem. 1995; 270(2):949-57. DOI: 10.1074/jbc.270.2.949. View

13.

Kelley M, Kow Y, Wilson 3rd D . Disparity between DNA base excision repair in yeast and mammals: translational implications. Cancer Res. 2003; 63(3):549-54. View

14.

Wiederhold L, Leppard J, Kedar P, Karimi-Busheri F, Rasouli-Nia A, Weinfeld M . AP endonuclease-independent DNA base excision repair in human cells. Mol Cell. 2004; 15(2):209-20. DOI: 10.1016/j.molcel.2004.06.003. View

15.

Haltiwanger B, Matsumoto Y, Nicolas E, Dianov G, Bohr V, Taraschi T . DNA base excision repair in human malaria parasites is predominantly by a long-patch pathway. Biochemistry. 2000; 39(4):763-72. DOI: 10.1021/bi9923151. View

16.

Gros L, Ishchenko A, Ide H, Elder R, Saparbaev M . The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway. Nucleic Acids Res. 2004; 32(1):73-81. PMC: 373275. DOI: 10.1093/nar/gkh165. View

17.

Hou E, Prasad R, Asagoshi K, Masaoka A, Wilson S . Comparative assessment of plasmid and oligonucleotide DNA substrates in measurement of in vitro base excision repair activity. Nucleic Acids Res. 2007; 35(17):e112. PMC: 2034467. DOI: 10.1093/nar/gkm639. View

18.

Tebbs R, Flannery M, Meneses J, Hartmann A, Tucker J, Thompson L . Requirement for the Xrcc1 DNA base excision repair gene during early mouse development. Dev Biol. 1999; 208(2):513-29. DOI: 10.1006/dbio.1999.9232. View

19.

Yoshimura M, Kohzaki M, Nakamura J, Asagoshi K, Sonoda E, Hou E . Vertebrate POLQ and POLbeta cooperate in base excision repair of oxidative DNA damage. Mol Cell. 2006; 24(1):115-25. PMC: 1868411. DOI: 10.1016/j.molcel.2006.07.032. View

20.

Jin Y, Garg P, Stith C, Al-Refai H, Sterling J, Murray L . The multiple biological roles of the 3'-->5' exonuclease of Saccharomyces cerevisiae DNA polymerase delta require switching between the polymerase and exonuclease domains. Mol Cell Biol. 2004; 25(1):461-71. PMC: 538786. DOI: 10.1128/MCB.25.1.461-471.2005. View