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Simple Summary: DNA damage occurs in healthy cells and cancer cells, but the quantity of damage and how efficiently it is repaired often differ between them. Due to genetic alterations, cancer cells can become 'addicted' to one or more forms of repair. This can be exploited by blocking DNA repair pathways that healthy cells can repair via redundant methods which are abrogated in cancer cells. Here, we identify such a scenario using a small molecule targeting CBX4, a protein key to a subset of DNA repair processes important for mending DNA double-strand breaks (DSBs). Consistent with the inhibition of these processes, treatment with the compound results in the selective killing of certain cancer cells when combined with ionizing radiation (IR). These findings raise the possibility that targeting CBX4 and/or the DSB repair pathways it regulates might be exploited more generally for the development of targeted anti-cancer strategies in the future. The therapeutic targeting of DNA repair pathways is an emerging concept in cancer treatment. Compounds that target specific DNA repair processes, such as those mending DNA double-strand breaks (DSBs), are therefore of therapeutic interest. UNC3866 is a small molecule that targets CBX4, a chromobox protein, and a SUMO E3 ligase. As a key modulator of DNA end resection—a prerequisite for DSB repair by homologous recombination (HR)—CBX4 promotes the functions of the DNA resection factor CtIP. Here, we show that treatment with UNC3866 markedly sensitises HR-deficient, NHEJ-hyperactive cancer cells to ionising radiation (IR), while it is non-toxic in selected HR-proficient cells. Consistent with UNC3866 targeting CtIP functions, it inhibits end-resection-dependent DNA repair including HR, alternative end joining (alt-EJ), and single-strand annealing (SSA). These findings raise the possibility that the UNC3866-mediated inhibition of end resection processes we define highlights a distinct vulnerability for the selective killing of HR-ineffective cancers. [ABSTRACT FROM AUTHOR]

Maintaining stability of the genome requires dedicated DNA repair and signalling processes that are essential for the faithful duplication and propagation of chromosomes. These DNA damage response (DDR) mechanisms counteract the potentially mutagenic impact of daily genotoxic stresses from both exogenous and endogenous sources. Inherent to these DNA repair pathways is the activity of protein factors that instigate repair processes in response to DNA lesions. The regulation, coordination, and orchestration of these DDR factors is carried out, in a large part, by post-translational modifications, such as phosphorylation, ubiquitylation, and modification with ubiquitin-like proteins (UBLs). The importance of ubiquitylation and UBLylation with SUMO in DNA repair is well established, with the modified targets and downstream signalling consequences relatively well characterised. However, the role of dedicated erasers for ubiquitin and UBLs, known as deubiquitylases (DUBs) and ubiquitin-like proteases (ULPs) respectively, in genome stability is less well established, particularly for emerging UBLs such as ISG15 and UFM1. In this review, we provide an overview of the known regulatory roles and mechanisms of DUBs and ULPs involved in genome stability pathways. Expanding our understanding of the molecular agents and mechanisms underlying the removal of ubiquitin and UBL modifications will be fundamental for progressing our knowledge of the DDR and likely provide new therapeutic avenues for relevant human diseases, such as cancer. [ABSTRACT FROM AUTHOR]

We have a limited understanding of how cells mark and identify newly replicated genomic loci that have a sister chromatid; here, unmethylated K20 in the tail of new histone H4 is shown to serve as a signature of post-replicative chromatin, which is specifically recognized by the homologous recombination complex TONSL-MMS22L. A marker for post-replicative chromatin We have a limited understanding of how cells mark and identify newly replicated genomic loci that have a sister chromatid. Here, Anja Groth and colleagues show that histone H4 tails unmethylated at lysine 20 (H4K20me0) serve as a signature of post-replicative chromatin and are specific to new histones incorporated during DNA replication. H4K20me0 is specifically recognized by a 'reader' domain of the TONSL-MMS22L homologous recombination complex, enabling differentiation of pre- and post-replicative chromatin, and allowing TONSL to function as a histone chaperone or guide repair of damaged replication forks. After DNA replication, chromosomal processes including DNA repair and transcription take place in the context of sister chromatids. While cell cycle regulation can guide these processes globally, mechanisms to distinguish pre- and post-replicative states locally remain unknown. Here we reveal that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the human TONSL-MMS22L.sup.1,2,3,4 homologous recombination complex. We identify the TONSL ankyrin repeat domain (ARD) as a reader of histone H4 tails unmethylated at K20 (H4K20me0), which are specific to new histones incorporated during DNA replication and mark post-replicative chromatin until the G2/M phase of the cell cycle. Accordingly, TONSL-MMS22L binds new histones H3-H4 both before and after incorporation into nucleosomes, remaining on replicated chromatin until late G2/M. H4K20me0 recognition is required for TONSL-MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. Consequently, TONSL ARD mutants are toxic, compromising genome stability, cell viability and resistance to replication stress. Together, these data reveal a histone-reader-based mechanism for recognizing the post-replicative state, offering a new angle to understand DNA repair with the potential for targeted cancer therapy., Author(s): Giulia Saredi [sup.1] , Hongda Huang [sup.2] , Colin M. Hammond [sup.1] , Constance Alabert [sup.1] , Simon Bekker-Jensen [sup.3] , Ignasi Forne [sup.4] , Nazaret Reverón-Gómez [sup.1] , [...]