Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast DCIS, and in pre-invasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx pre-invasive to invasive NSCLC lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models, revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in pre-invasive disease, providing fuel for selection early in cancer evolution

Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

Catalytic Transformations of Alkynes via Ruthenium Vinylidene and Allenylidene Intermediates

NOTICE: This is the peer reviewed version of the following book chapter: Varela J. A., González-Rodríguez C., Saá C. (2014). Catalytic Transformations of Alkynes via Ruthenium Vinylidene and Allenylidene Intermediates. In: Dixneuf P., Bruneau C. (eds) Ruthenium in Catalysis. Topics in Organometallic Chemistry, vol 48, pp. 237-287. Springer, Cham. [doi: 10.1007/3418_2014_81]. This article may be used for non-commercial purposes in accordance with Springer Verlag Terms and Conditions for self-archiving.Vinylidenes are high-energy tautomers of terminal alkynes and they can be stabilized by coordination with transition metals. The resulting metal-vinylidene species have interesting chemical properties that make their reactivity different to that of the free and metal π-coordinated alkynes: the carbon α to the metal is electrophilic whereas the β carbon is nucleophilic. Ruthenium is one of the most commonly used transition metals to stabilize vinylidenes and the resulting species can undergo a range of useful transformations. The most remarkable transformations are the regioselective anti-Markovnikov addition of different nucleophiles to catalytic ruthenium vinylidenes and the participation of the π system of catalytic ruthenium vinylidenes in pericyclic reactions. Ruthenium vinylidenes have also been employed as precatalysts in ring closing metathesis (RCM) or ring opening metathesis polymerization (ROMP). Allenylidenes could be considered as divalent radicals derived from allenes. In a similar way to vinylidenes, allenylidenes can be stabilized by coordination with transition metals and again ruthenium is one of the most widely used metals. Metalallenylidene complexes can be easily obtained from terminal propargylic alcohols by dehydration of the initially formed metal-hydroxyvinylidenes, in which the reactivity of these metal complexes is based on the electrophilic nature of Cα and Cγ, while Cβ is nucleophilic. Catalytic processes based on nucleophilic additions and pericyclic reactions involving the π system of ruthenium allenylidenes afford interesting new structures with high selectivity and atom economy