抄録
One of the most striking features of the cellular response to DNA double strand breaks (DSBs) is the accumulation of proteins into large and microscopically discernible structures in the vicinity of the lesions – the so-called ionizing radiation induced foci (IRIF). This accumulation process is orchestrated by post-translational histone modifications, which serve as affinity platforms for DNA damage response (DDR) proteins. The most proximal of these modifications seems to be the phosphorylation of the histone variant H2AX by the ATM kinase (γ-H2AX), which leads to the recruitment of Mdc1 and its associated protein partners. One of these is the ubiquitin ligase RNF8, which mediates K63-linked poly-ubiquitylation of histones, which in turn is required to target downstream DDR factors such as 53BP1 and BRCA1 to sites of DNA damage. Since our initial discovery of RNF8-mediated histone ubiquitylation, we and others have uncovered the identity and functions of additional components of this pathway, highlighting the exquisite complexity of this reaction.
While the relatively inactive RNF8 ligase is critically required to prime the ubiquitylation reaction, a much more active ligase, RNF168, plays a crucial role in amplifying the response. We recently identified Herc2 as a novel factor that is required for DDR-associated histone ubiquitylation. Herc2 is a giant 500 kDa protein that plays a key role in the DDR by orchestrating the assembly of an active RNF8 ubiquitin ligase complex, and directing this activity towards histones H2A and H2AX. In my talk, I will review how DDR-induced histone ubiquitylation is orchestrated, and present our latest findings on the functions of Herc2. I will also present how DNA damage induced SUMOylation of several of the above components regulates the response.
