Abstract
Monoubiquitination of H2A is a major histone modification in mammalian cells. Understanding how monoubiquitinated H2A (uH2A) regulates DNA-based processes in the context of chromatin is a challenging question. Work in the past years linked uH2A to transcriptional repression by the Polycomb group proteins of developmental regulators. Recently, a number of mammalian deubiquitinating enzymes (DUBs) that catalyze the removal of ubiquitin from H2A have been discovered. These studies provide convincing evidence that H2A deubiquitination is connected with gene activation. In addition, uH2A regulatory enzymes have crucial roles in the cellular response to DNA damage and in cell cycle progression. In this review we will discuss new insights into uH2A biology, with emphasis on the H2A DUBs.
Highlights
Conjugation of ubiquitin (Ub) occurs through the concerted action of an ATP-dependent Ub-activating enzyme (E1), a Ub conjugating enzyme (E2), and a Ub ligase (E3) [1]
The discussed data show that Understanding how monoubiquitinated H2A (uH2A) impacts on several important aspects of cellular physiology
We will put forward key questions concerning regulation of activity, recruitment and substrate specificity, whose addressing is predicted to greatly advance our knowledge of how deubiquitinating enzymes (DUBs) impact on the pleotropic function of H2A
Summary
Conjugation of ubiquitin (Ub) occurs through the concerted action of an ATP-dependent Ub-activating enzyme (E1), a Ub conjugating enzyme (E2), and a Ub ligase (E3) [1]. One plausible possibility is that uH2A/H2AX may facilitate a more global alteration of the chromatin, known to occur at DSBs [57,71], allowing exposure of other histone marks This mechanism might be relevant for 53BP1 relocalization to IRIF, as suggested by the findings that 53BP1 binds to methylated histones [72,73] and that its recruitment is independent from Rap80 [18,19,55,68]. We can envision several experimental approaches towards the elucidation of the molecular mechanism(s) of uH2A/uH2AX-mediated DDR These include: i) biochemical characterization of the E3 (RNF8, BRCA1) and DUB activities (USP3, others?) on nucleosomes; ii) identification of the IR-induced ubiquitination site(s) on H2A/H2AX; iii) isolation of uH2A/uH2AX binding proteins; iv) definition of the extent of the ubiquitin mark around the DSB. It will be interesting to analyze this phenotype in more detail to assess which phase of the cell cycle is affected
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