L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage

Somaira Nowsheen, Khaled Aziz, Asef Aziz, Min Deng, Bo Qin, Kuntian Luo, Karthik B. Jeganathan, Henan Zhang, Tongzheng Liu, Jia Yu, Yibin Deng, Jian Yuan, Wei Ding, Jan M. Van Deursen, Zhenkun Lou

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Cells respond to cytotoxic DNA double-strand breaks (DSBs) by recruiting DNA repair proteins to the damaged site. This recruitment is dependent on ubiquitylation of adjacent chromatin areas by E3 ubiquitin ligases such as RNF8 and RNF168, which are recruited sequentially to the DSBs. However, it is unclear what dictates the sequential order and recruits RNF168 to the DNA lesion. Here, we reveal that L3MBTL2 (lethal(3)malignant brain tumour-like protein 2) is the missing link between RNF8 and RNF168. We found that L3MBTL2 is recruited by MDC1 and subsequently ubiquitylated by RNF8. Ubiquitylated L3MBTL2, in turn, facilitates recruitment of RNF168 to the DNA lesion and promotes DNA DSB repair. These results identify L3MBTL2 as a key target of RNF8 following DNA damage and demonstrates how the DNA damage response pathway is orchestrated by ubiquitin signalling.

Original languageEnglish (US)
Pages (from-to)455-464
Number of pages10
JournalNature Cell Biology
Volume20
Issue number4
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Cell Biology

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    Nowsheen, S., Aziz, K., Aziz, A., Deng, M., Qin, B., Luo, K., Jeganathan, K. B., Zhang, H., Liu, T., Yu, J., Deng, Y., Yuan, J., Ding, W., Van Deursen, J. M., & Lou, Z. (2018). L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage. Nature Cell Biology, 20(4), 455-464. https://doi.org/10.1038/s41556-018-0071-x