The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

Keren Baranes-Bachar, Adva Levy-Barda, Judith Oehler, Dylan A. Reid, Isabel Soria-Bretones, Ty C. Voss, Dudley Chung, Yoon Park, Chao Liu, Jong Bok Yoon, Wei Li, Graham Dellaire, Tom Misteli, Pablo Huertas, Eli Rothenberg, Kristijan Ramadan, Yael Ziv, Yosef Shiloh

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A's recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair. The DNA damage response is activated by DNA double-strand breaks (DSBs) and involves protein ubiquitylation. Baranes-Bachar et al. show that, following initial ubiquitylation at DSB sites by E3 ubiquitin ligases, ubiquitin chains require further modulation by an E3/E4 ligase, UBE4A, to achieve optimal DSB repair.

Original languageEnglish
Pages (from-to)866-878.e7
JournalMolecular Cell
Volume69
Issue number5
DOIs
Publication statusPublished - 2018 Mar 1

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Ubiquitin-Protein Ligases
Ubiquitination
DNA Damage
BRCA1 Protein
Proteins
Double-Stranded DNA Breaks
Ubiquitin
Recombinational DNA Repair
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Baranes-Bachar, K., Levy-Barda, A., Oehler, J., Reid, D. A., Soria-Bretones, I., Voss, T. C., ... Shiloh, Y. (2018). The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. Molecular Cell, 69(5), 866-878.e7. https://doi.org/10.1016/j.molcel.2018.02.002
Baranes-Bachar, Keren ; Levy-Barda, Adva ; Oehler, Judith ; Reid, Dylan A. ; Soria-Bretones, Isabel ; Voss, Ty C. ; Chung, Dudley ; Park, Yoon ; Liu, Chao ; Yoon, Jong Bok ; Li, Wei ; Dellaire, Graham ; Misteli, Tom ; Huertas, Pablo ; Rothenberg, Eli ; Ramadan, Kristijan ; Ziv, Yael ; Shiloh, Yosef. / The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. In: Molecular Cell. 2018 ; Vol. 69, No. 5. pp. 866-878.e7.
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abstract = "Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A's recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair. The DNA damage response is activated by DNA double-strand breaks (DSBs) and involves protein ubiquitylation. Baranes-Bachar et al. show that, following initial ubiquitylation at DSB sites by E3 ubiquitin ligases, ubiquitin chains require further modulation by an E3/E4 ligase, UBE4A, to achieve optimal DSB repair.",
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Baranes-Bachar, K, Levy-Barda, A, Oehler, J, Reid, DA, Soria-Bretones, I, Voss, TC, Chung, D, Park, Y, Liu, C, Yoon, JB, Li, W, Dellaire, G, Misteli, T, Huertas, P, Rothenberg, E, Ramadan, K, Ziv, Y & Shiloh, Y 2018, 'The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair', Molecular Cell, vol. 69, no. 5, pp. 866-878.e7. https://doi.org/10.1016/j.molcel.2018.02.002

The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. / Baranes-Bachar, Keren; Levy-Barda, Adva; Oehler, Judith; Reid, Dylan A.; Soria-Bretones, Isabel; Voss, Ty C.; Chung, Dudley; Park, Yoon; Liu, Chao; Yoon, Jong Bok; Li, Wei; Dellaire, Graham; Misteli, Tom; Huertas, Pablo; Rothenberg, Eli; Ramadan, Kristijan; Ziv, Yael; Shiloh, Yosef.

In: Molecular Cell, Vol. 69, No. 5, 01.03.2018, p. 866-878.e7.

Research output: Contribution to journalArticle

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AU - Oehler, Judith

AU - Reid, Dylan A.

AU - Soria-Bretones, Isabel

AU - Voss, Ty C.

AU - Chung, Dudley

AU - Park, Yoon

AU - Liu, Chao

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AU - Li, Wei

AU - Dellaire, Graham

AU - Misteli, Tom

AU - Huertas, Pablo

AU - Rothenberg, Eli

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