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New ligases join the ubiquitylation cascade in repair

Histone ubiquitylation is an important component of the DNA double-strand break repair (DSBR) response. Previous work has identified a sequential cascade of the ubiquitin ligases RNF8 and RNF168, which are important for ubiquitylating histones H2A and H2AX, and for amplifying the ubiquitylation signals through K63-linked ubiquitin chains, respectively, at DSBs. These ubiquitylation events are crucial for recruiting and retaining additional regulators of the repair pathway at DSBs such as 53BP1. But precisely how these ubiquitylation events are restricted to break sites is not understood. New work from Lukas and colleagues (Cell 150, 687–709, 2012 ) now provides insights into this process.

In an siRNA screen against known components of the human ubiquitinome, the authors identified two additional ubiquitin ligases, TRIP12 and UBR5, that act upstream of RNF168 to control its accumulation at DSBs. Depletion of the ligases led to enhanced accumulation of RNF168 on chromatin and a concomitant expansion of ubiquitin-enriched chromatin domains, including components of the repair pathway such as RAP80, BRCA1 and 53BP1. Whereas UBR5 was found to modestly affect levels of multiple ligases involved in DSBR, the TRIP12 effect was specific for RNF168. Finally, the authors found that levels of RNF168 are rate limiting in the pathway and increased accumulation of RNF168 seemed to enhance efficiency of repair.

The exact molecular mechanism underlying UBR5 and TRIP12 control of RNF168 levels awaits future study.


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Swaminathan, S. New ligases join the ubiquitylation cascade in repair. Nat Cell Biol 14, 990 (2012).

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