Abstract
Ubiquitin and the ubiquitin-like modifier SUMO are intimately connected with the cellular response to various types of DNA damage. A striking feature is the local accumulation of these proteinaceous post-translational modifications in the direct vicinity to DNA double-strand breaks, which plays a critical role in the formation of ionizing radiation-induced foci. The functional significance of these modifications is the coordinated recruitment and removal of proteins involved in DNA damage signaling and repair in a timely manner. The central orchestrators of these processes are the ubiquitin and SUMO ligases that are responsible for accurately tagging a broad array of chromatin and chromatin-associated proteins thereby changing their behavior or destination. Despite many differences in the mode of action of these enzymes, they share some striking features that are of direct relevance for their function in the DNA damage response. In this review, we outline the molecular mechanisms that are responsible for the recruitment of ubiquitin and SUMO ligases and discuss the importance of chromatin proximity in this process.
Highlights
The cellular response to compromised genome integrity is a vital process that is tightly regulated by a number of post-translational modifications (PTMs) that dictate the course of action at the sites of DNA damage
In contrast to phosphorylation at ionizing radiationinduced foci (IRIF), which is primarily facilitated by the PI3K-like kinase ATM with the variant histone H2AX being the predominant target (Shiloh, 2003), decoration of the chromatin with ubiquitin and small ubiquitin-like modifiers (SUMO) is attributed to several enzymes that differ in their specificity for substrates at the chromatin (Bekker-Jensen and Mailand, 2011; Jackson and Durocher, 2013)
Despite the many differences between the ubiquitin and SUMO ligases involved in the DNA damage response, they share a number of characteristics such as the critical role of chromatin recruitment for their functionality and their tendency to target multiple substrates at the DNA double-strand break (DSB)
Summary
Ligases Home in on DNA Double-Strand Breaks. Ubiquitin and the ubiquitin-like modifier SUMO are intimately connected with the cellular response to various types of DNA damage. A striking feature is the local accumulation of these proteinaceous post-translational modifications in the direct vicinity to DNA doublestrand breaks, which plays a critical role in the formation of ionizing radiation-induced foci. The functional significance of these modifications is the coordinated recruitment and removal of proteins involved in DNA damage signaling and repair in a timely manner. The central orchestrators of these processes are the ubiquitin and SUMO ligases that are responsible for accurately tagging a broad array of chromatin and chromatin-associated proteins thereby changing their behavior or destination. Despite many differences in the mode of action of these enzymes, they share some striking features that are of direct relevance for their function in the DNA damage response. We outline the molecular mechanisms that are responsible for the recruitment of ubiquitin and SUMO ligases and discuss the importance of chromatin proximity in this process
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