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 journalArticlepeer-review

25 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

Bibliographical note

Funding Information:
We thank Z. Zhang, M. Jasin, X. Yu, D. Reinberg, N. Dantuma and N. Mailand for providing reagents. Thank you to the members of the Lou lab for helpful discussions and B. Davies for technical assistance. This work was supported, in part, by NIH grants CA130996, CA108961 and CA148940 (to Z.L.) and CA160333 (to Y.D.). S.N. was supported by the Laura J. Siegel Breast Cancer Fellowship Award from the Foundation for Women’s Wellness. K.A. and S.N. thank the Mayo Clinic MSTP for fostering an outstanding environment for physician-scientist training. We thank the Mayo Clinic Cancer Center for the use of the Cytogenetics Core, which provided PNA FISH services. The Mayo Clinic Cancer Center is supported in part by an NCI Cancer Center Support Grant 5P30 CA15083-36.

Publisher Copyright:
© 2018 The Author(s).

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