ERCC1-XPF Endonuclease Facilitates DNA Double-strand Break Repair

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2008 Jun 11

PMID 18541667

Citations 159

Authors

Anwaar Ahmad

Andria Rasile Robinson

Anette Duensing

Ellen van Drunen

H Berna Beverloo

David B Weisberg

Paul Hasty

Jan H J Hoeijmakers

Laura J Niedernhofer

Affiliations

Soon will be listed here.

Abstract

ERCC1-XPF endonuclease is required for nucleotide excision repair (NER) of helix-distorting DNA lesions. However, mutations in ERCC1 or XPF in humans or mice cause a more severe phenotype than absence of NER, prompting a search for novel repair activities of the nuclease. In Saccharomyces cerevisiae, orthologs of ERCC1-XPF (Rad10-Rad1) participate in the repair of double-strand breaks (DSBs). Rad10-Rad1 contributes to two error-prone DSB repair pathways: microhomology-mediated end joining (a Ku86-independent mechanism) and single-strand annealing. To determine if ERCC1-XPF participates in DSB repair in mammals, mutant cells and mice were screened for sensitivity to gamma irradiation. ERCC1-XPF-deficient fibroblasts were hypersensitive to gamma irradiation, and gammaH2AX foci, a marker of DSBs, persisted in irradiated mutant cells, consistent with a defect in DSB repair. Mutant mice were also hypersensitive to irradiation, establishing an essential role for ERCC1-XPF in protecting against DSBs in vivo. Mice defective in both ERCC1-XPF and Ku86 were not viable. However, Ercc1(-/-) Ku86(-/-) fibroblasts were hypersensitive to gamma irradiation compared to single mutants and accumulated significantly greater chromosomal aberrations. Finally, in vitro repair of DSBs with 3' overhangs led to large deletions in the absence of ERCC1-XPF. These data support the conclusion that, as in yeast, ERCC1-XPF facilitates DSB repair via an end-joining mechanism that is Ku86 independent.

Citing Articles

Clonal dynamics and somatic evolution of haematopoiesis in mouse.

Kapadia C, Williams N, Dawson K, Watson C, Yousefzadeh M, Le D Nature. 2025; .

PMID: 40044850 DOI: 10.1038/s41586-025-08625-8.

The Ercc1 mouse model of XFE progeroid syndrome undergoes accelerated retinal degeneration.

Narasimhan A, Min S, Johnson L, Roehrich H, Cho W, Her T Aging Cell. 2024; 24(3):e14419.

PMID: 39604117 PMC: 11896507. DOI: 10.1111/acel.14419.

Clonal dynamics and somatic evolution of haematopoiesis in mouse.

Kapadia C, Williams N, Dawson K, Watson C, Yousefzadeh M, Le D bioRxiv. 2024; .

PMID: 39345649 PMC: 11429886. DOI: 10.1101/2024.09.17.613129.

Targeting drug resistance in glioblastoma (Review).

Sherman J, Bobak A, Arsiwala T, Lockman P, Aulakh S Int J Oncol. 2024; 65(2).

PMID: 38994761 PMC: 11251740. DOI: 10.3892/ijo.2024.5668.

p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice.

Hill R, Bona N, Smink J, Webb H, Crisp A, Garaycoechea J Nat Commun. 2024; 15(1):2518.

PMID: 38514641 PMC: 10957910. DOI: 10.1038/s41467-024-46844-1.

References

Newman M, Murray-Rust J, Lally J, Rudolf J, Fadden A, Knowles P . Structure of an XPF endonuclease with and without DNA suggests a model for substrate recognition. EMBO J. 2005; 24(5):895-905. PMC: 554130. DOI: 10.1038/sj.emboj.7600581. View

Sonoda E, Sasaki M, Morrison C, Yamaguchi-Iwai Y, Takata M, Takeda S . Sister chromatid exchanges are mediated by homologous recombination in vertebrate cells. Mol Cell Biol. 1999; 19(7):5166-9. PMC: 84359. DOI: 10.1128/MCB.19.7.5166. View

de Laat W, Appeldoorn E, Jaspers N, Hoeijmakers J . DNA structural elements required for ERCC1-XPF endonuclease activity. J Biol Chem. 1998; 273(14):7835-42. DOI: 10.1074/jbc.273.14.7835. View

Niedernhofer L, Odijk H, Budzowska M, van Drunen E, Maas A, Theil A . The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Mol Cell Biol. 2004; 24(13):5776-87. PMC: 480908. DOI: 10.1128/MCB.24.13.5776-5787.2004. View

Enzlin J, Scharer O . The active site of the DNA repair endonuclease XPF-ERCC1 forms a highly conserved nuclease motif. EMBO J. 2002; 21(8):2045-53. PMC: 125967. DOI: 10.1093/emboj/21.8.2045. View

Liang F, Han M, Romanienko P, Jasin M . Homology-directed repair is a major double-strand break repair pathway in mammalian cells. Proc Natl Acad Sci U S A. 1998; 95(9):5172-7. PMC: 20233. DOI: 10.1073/pnas.95.9.5172. View

Rogakou E, Boon C, Redon C, Bonner W . Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol. 1999; 146(5):905-16. PMC: 2169482. DOI: 10.1083/jcb.146.5.905. View

Weinstock D, Jasin M . Alternative pathways for the repair of RAG-induced DNA breaks. Mol Cell Biol. 2005; 26(1):131-9. PMC: 1317616. DOI: 10.1128/MCB.26.1.131-139.2006. View

Secretan M, Scuric Z, Oshima J, Bishop A, Howlett N, Yau D . Effect of Ku86 and DNA-PKcs deficiency on non-homologous end-joining and homologous recombination using a transient transfection assay. Mutat Res. 2004; 554(1-2):351-64. DOI: 10.1016/j.mrfmmm.2004.05.016. View

10.

Li X, Shen S, Wang S, Ouyang H, Li G . Restoration of T cell-specific V(D)J recombination in DNA-PKcs(-/-) mice by ionizing radiation: The effects on survival, development, and tumorigenesis. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002; 34(2):149-57. View

11.

Stark J, Pierce A, Oh J, Pastink A, Jasin M . Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol Cell Biol. 2004; 24(21):9305-16. PMC: 522275. DOI: 10.1128/MCB.24.21.9305-9316.2004. View

12.

Dolle M, Busuttil R, Garcia A, Wijnhoven S, van Drunen E, Niedernhofer L . Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat Res. 2006; 596(1-2):22-35. DOI: 10.1016/j.mrfmmm.2005.11.008. View

13.

Rothkamm K, Kruger I, Thompson L, Lobrich M . Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol. 2003; 23(16):5706-15. PMC: 166351. DOI: 10.1128/MCB.23.16.5706-5715.2003. View

14.

Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J . Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003; 5(8):741-7. PMC: 4940195. DOI: 10.1038/ncb1024. View

15.

Matsumura Y, Nishigori C, Yagi T, Imamura S, Takebe H . Characterization of molecular defects in xeroderma pigmentosum group F in relation to its clinically mild symptoms. Hum Mol Genet. 1998; 7(6):969-74. DOI: 10.1093/hmg/7.6.969. View

16.

Vogel H, Lim D, Karsenty G, Finegold M, Hasty P . Deletion of Ku86 causes early onset of senescence in mice. Proc Natl Acad Sci U S A. 1999; 96(19):10770-5. PMC: 17958. DOI: 10.1073/pnas.96.19.10770. View

17.

Schrader C, Vardo J, Linehan E, Twarog M, Niedernhofer L, Hoeijmakers J . Deletion of the nucleotide excision repair gene Ercc1 reduces immunoglobulin class switching and alters mutations near switch recombination junctions. J Exp Med. 2004; 200(3):321-30. PMC: 2211985. DOI: 10.1084/jem.20040052. View

18.

Nussenzweig A, SOKOL K, Burgman P, Li L, Li G . Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development. Proc Natl Acad Sci U S A. 1998; 94(25):13588-93. PMC: 28350. DOI: 10.1073/pnas.94.25.13588. View

19.

Sijbers A, de Laat W, Ariza R, Biggerstaff M, Wei Y, Moggs J . Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Cell. 1996; 86(5):811-22. DOI: 10.1016/s0092-8674(00)80155-5. View

20.

Prasher J, Lalai A, Heijmans-Antonissen C, Ploemacher R, Hoeijmakers J, Touw I . Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1-/- mice. EMBO J. 2005; 24(4):861-71. PMC: 549615. DOI: 10.1038/sj.emboj.7600542. View