RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair

Alihossein Saberi, Helfrid Hochegger, D. Szüts, Li Lan, Akira Yasui, Julian E. Sale, Yoshihito Taniguchi, Yasuhiro Murakawa, Weihua Zeng, Kyoko Yokomori, Thomas Helleday, Hirobumi Teraoka, Hiroshi Arakawa, Jean Marie Buerstedde, Shunichi Takeda

Research output: Contribution to journalArticle

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Abstract

The Saccharomyces cerevisiae RAD18 gene is essential for postreplication repair but is not required for homologous recombination (HR), which is the major double-strand break (DSB) repair pathway in yeast. Accordingly, yeast rad18 mutants are tolerant of camptothecin (CPT), a topoisomerase I inhibitor, which induces DSBs by blocking replication. Surprisingly, mammalian cells and chicken DT40 cells deficient in Rad18 display reduced HR-dependent repair and are hypersensitive to CPT. Deletion of nonhomologous end joining (NHEJ), a major DSB repair pathway in vertebrates, in rad18-deficient DT40 cells completely restored HR-mediated DSB repair, suggesting that vertebrate Rad18 regulates the balance between NHEJ and HR. We previously reported that loss of NHEJ normalized the CPT sensitivity of cells deficient in poly(ADP-ribose) polymerase 1 (PARP1). Concomitant deletion of Rad18 and PARP1 synergistically increased CPT sensitivity, and additional inactivation of NHEJ normalized this hypersensitivity, indicating their parallel actions. In conclusion, higher-eukaryotic cells separately employ PARP1 and Rad18 to suppress the toxic effects of NHEJ during the HR reaction at stalled replication forks.

Original languageEnglish
Pages (from-to)2562-2571
Number of pages10
JournalMolecular and Cellular Biology
Volume27
Issue number7
DOIs
Publication statusPublished - Apr 2007

Fingerprint

Recombinational DNA Repair
Camptothecin
Poly(ADP-ribose) Polymerases
Homologous Recombination
Vertebrates
Yeasts
Topoisomerase I Inhibitors
Poisons
Essential Genes
Eukaryotic Cells
Saccharomyces cerevisiae
Chickens
Hypersensitivity
Poly (ADP-Ribose) Polymerase-1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair. / Saberi, Alihossein; Hochegger, Helfrid; Szüts, D.; Lan, Li; Yasui, Akira; Sale, Julian E.; Taniguchi, Yoshihito; Murakawa, Yasuhiro; Zeng, Weihua; Yokomori, Kyoko; Helleday, Thomas; Teraoka, Hirobumi; Arakawa, Hiroshi; Buerstedde, Jean Marie; Takeda, Shunichi.

In: Molecular and Cellular Biology, Vol. 27, No. 7, 04.2007, p. 2562-2571.

Research output: Contribution to journalArticle

Saberi, A, Hochegger, H, Szüts, D, Lan, L, Yasui, A, Sale, JE, Taniguchi, Y, Murakawa, Y, Zeng, W, Yokomori, K, Helleday, T, Teraoka, H, Arakawa, H, Buerstedde, JM & Takeda, S 2007, 'RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair', Molecular and Cellular Biology, vol. 27, no. 7, pp. 2562-2571. https://doi.org/10.1128/MCB.01243-06
Saberi, Alihossein ; Hochegger, Helfrid ; Szüts, D. ; Lan, Li ; Yasui, Akira ; Sale, Julian E. ; Taniguchi, Yoshihito ; Murakawa, Yasuhiro ; Zeng, Weihua ; Yokomori, Kyoko ; Helleday, Thomas ; Teraoka, Hirobumi ; Arakawa, Hiroshi ; Buerstedde, Jean Marie ; Takeda, Shunichi. / RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 7. pp. 2562-2571.
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AU - Lan, Li

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AU - Helleday, Thomas

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