Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks

Emma Bolderson, Nozomi Tomimatsu, Derek J. Richard, Didier Boucher, Rakesh Kumar, Tej K. Pandita, Sandeep Burma, Kum Kum Khanna

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

DNA double-strand break (DSB) repair via the homologous recombination pathway is a multistage process, which results in repair of the DSB without loss of genetic information or fidelity. One essential step in this process is the generation of extended single-stranded DNA (ssDNA) regions at the break site. This ssDNA serves to induce cell cycle checkpoints and is required for Rad51 mediated strand invasion of the sister chromatid. Here, we show that human Exonuclease 1 (Exo1) is required for the normal repair of DSBs by HR. Cells depleted of Exo1 show chromosomal instability and hypersensitivity to ionising radiation (IR) exposure. We find that Exo1 accumulates rapidly at DSBs and is required for the recruitment of RPA and Rad51 to sites of DSBs, suggesting a role for Exo1 in ssDNA generation. Interestingly, the phosphorylation of Exo1 by ATM appears to regulate the activity of Exo1 following resection, allowing optimal Rad51 loading and the completion of HR repair. These data establish a role for Exo1 in resection of DSBs in human cells, highlighting the critical requirement of Exo1 for DSB repair via HR and thus the maintenance of genomic stability.

Original languageEnglish (US)
Article numbergkp1164
Pages (from-to)1821-1831
Number of pages11
JournalNucleic Acids Research
Volume38
Issue number6
DOIs
StatePublished - Feb 24 2010

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Recombinational DNA Repair
Phosphorylation
Single-Stranded DNA
Chromosomal Instability
Chromatids
Double-Stranded DNA Breaks
Genomic Instability
Cell Cycle Checkpoints
Ionizing Radiation
exodeoxyribonuclease I
Hypersensitivity
Maintenance
1,2-di-(4-sulfamidophenyl)-4-butylpyrazolidine-3,5-dione

ASJC Scopus subject areas

  • Genetics

Cite this

Bolderson, E., Tomimatsu, N., Richard, D. J., Boucher, D., Kumar, R., Pandita, T. K., ... Khanna, K. K. (2010). Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks. Nucleic Acids Research, 38(6), 1821-1831. [gkp1164]. https://doi.org/10.1093/nar/gkp1164

Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks. / Bolderson, Emma; Tomimatsu, Nozomi; Richard, Derek J.; Boucher, Didier; Kumar, Rakesh; Pandita, Tej K.; Burma, Sandeep; Khanna, Kum Kum.

In: Nucleic Acids Research, Vol. 38, No. 6, gkp1164, 24.02.2010, p. 1821-1831.

Research output: Contribution to journalArticle

Bolderson, E, Tomimatsu, N, Richard, DJ, Boucher, D, Kumar, R, Pandita, TK, Burma, S & Khanna, KK 2010, 'Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks', Nucleic Acids Research, vol. 38, no. 6, gkp1164, pp. 1821-1831. https://doi.org/10.1093/nar/gkp1164
Bolderson E, Tomimatsu N, Richard DJ, Boucher D, Kumar R, Pandita TK et al. Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks. Nucleic Acids Research. 2010 Feb 24;38(6):1821-1831. gkp1164. https://doi.org/10.1093/nar/gkp1164
Bolderson, Emma ; Tomimatsu, Nozomi ; Richard, Derek J. ; Boucher, Didier ; Kumar, Rakesh ; Pandita, Tej K. ; Burma, Sandeep ; Khanna, Kum Kum. / Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks. In: Nucleic Acids Research. 2010 ; Vol. 38, No. 6. pp. 1821-1831.
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