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

13 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

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair'. Together they form a unique fingerprint.

  • Cite this

    Baranes-Bachar, K., Levy-Barda, A., Oehler, J., Reid, D. A., Soria-Bretones, I., Voss, T. C., Chung, D., Park, Y., Liu, C., Yoon, J. B., 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, 69(5), 866-878.e7. https://doi.org/10.1016/j.molcel.2018.02.002