The chemical treatment of cancer started with the realization that DNA damaging agents such as mustard gas present notable antitumoural properties. Consequently, early drug development focused on genotoxic chemicals, some of which are still widely used in the clinic. However, the efficacy of such therapies is often limited by the side effects of these drugs on healthy cells. A refinement to this approach is to use compounds that can exploit the presence of DNA damage in cancer cells. Given that replication stress (RS) is a major source of genomic instability in cancer, targeting the RS-response kinase ataxia telangiectasia and Rad3-related protein (ATR) has emerged as a promising alternative. With ATR inhibitors now entering clinical trials, we here revisit the biology behind this strategy and discuss potential biomarkers that could be used for a better selection of patients who respond to therapy.

The Malignant Brain Tumor (MBT) domain is a “chromatin reader”, a protein module that binds to post-translational modifications on histone tails that are thought to affect a variety of chromatin processes, including transcription. More specifically, MBT domains recognize mono- and di-methylated lysines at a number of different positions on histone H3 and H4 tails. Three Drosophila proteins, SCM, L(3)MBT and SFMBT contain multiple adjacent MBT repeats and have critical roles in development, maintenance of cell identity, and tumor suppression. Although they function in different pathways, these proteins all localize to chromatin in vivo and repress transcription by a currently unknown molecular mechanism that requires the MBT domains. The human genome contains several homologues of these MBT proteins, some of which have been linked to important gene regulatory pathways, such as E2F/Rb- and Polycomb-mediated repression, and to the insurgence of certain neurological tumors. Here, we review the genetics, biochemistry, and cell biology of MBT proteins and their role in development and disease.

Annexin-1 is an anti-inflammatory protein that plays an important homeostatic role in innate immunity; however, its potential actions in the modulation of adaptive immunity have never been explored.

Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates various aspects of DNA replication. We previously showed that the chromatin around replisomes is rich in SUMO and depleted in Ub, whereas an opposite pattern is observed in mature chromatin. How this SUMO-rich/Ub-low environment is maintained at sites of DNA replication is not known. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Chemical inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced to chromatin away from replisomes. Our findings provide a model to explain the differential accumulation of SUMO and Ub at replication forks, and identify an essential role of USP7 in DNA replication that should be taken into account for the use of USP7 inhibitors as anticancer agents.