Abstract
Ubiquitination is a reversible protein modification broadly implicated in cellular functions. Signaling processes mediated by ubiquitin (ub) are crucial for the cellular response to DNA double-strand breaks (DSBs), one of the most dangerous types of DNA lesions. In particular, the DSB response critically relies on active ubiquitination by the RNF8 and RNF168 ub ligases at the chromatin, which is essential for proper DSB signaling and repair. How this pathway is fine-tuned and what the functional consequences are of its deregulation for genome integrity and tissue homeostasis are subject of intense investigation. One important regulatory mechanism is by reversal of substrate ubiquitination through the activity of specific deubiquitinating enzymes (DUBs), as supported by the implication of a growing number of DUBs in DNA damage response processes. Here, we discuss the current knowledge of how ub-mediated signaling at DSBs is controlled by DUBs, with main focus on DUBs targeting histone H2A and on their recent implication in stem cell biology and cancer.
Highlights
The ability of cells to maintain the integrity of their genome is crucial for organism physiology, including stem cell and tissue homeostasis and cancer avoidance (Jackson and Bartek, 2009; Blanpain et al, 2011; Behrens et al, 2014)
We recently found that deletion of Usp3 in mice leads to a measurable increase in mono-ubiquitinated histone H2A (uH2A) and mono-ubiquitinated histone H2B (uH2B) in freshly isolated tissues, suggesting that USP3 has a non-redundant role in preventing accumulation of uH2A and uH2B in vivo (Lancini et al, 2014)
Given the excess of chromatin-bound ub conjugates compared to the increase of uH2A measured upon USP3 loss (Nicassio et al, 2007; Lancini et al, 2014), it is conceivable that modulation of DNA damage response (DDR) signaling by USP3 may involve deubiquitination of additional, non-histone, targets
Summary
Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, Netherlands. Specialty section: This article was submitted to Cancer Genetics, a section of the journal
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
