Biology subjects

Benamar, M.

Publications and source records attributed to Benamar, M..

3 recordsLinked to original sources

bioRxiv2024

Break-induced replication drives large-scale genomic amplifications in cancer cells

DNA double-strand breaks (DSBs) are highly toxic lesions that underly the efficacy of ionizing radiation (IR) and a large number of cytotoxic chemotherapies1-3. Yet, abnormal repair of DSBs is associated with genomic instability and may contribute to cancer heterogeneity and tumour evolution. Here, we show that DSBs induced by IR, by DSB-inducing chemotherapeutics, or by the expression of a rare-cutting restriction endonuclease induce large-scale genomic amplification in human cancer cells. Importantly, the extent of DSB-induced genomic amplification (DIGA) in a panel of melanoma cell lines correlated with the degree of cytotoxicity elicited by IR, suggesting that DIGA contributes significantly to DSB-induced cancer cell lethality. DIGA, which is mediated through conservative DNA synthesis, does not require origin re-licensing, and is enhanced by the depletion or deletion of the methyltransferases SET8 and SUV4-20H1, which function sequentially to mono- and di-methylate histone H4 lysine 20 (H4K20) at DSBs to facilitate the recruitment of 53BP1-RIF1 and its downstream effector shieldin complex to DSBs to prevent hyper-resection4-11. Consistently, DIGA was enhanced in cells lacking 53BP1 or RIF1, or in cells that lacked components of the shieldin complex or of other factors that help recruit 53BP1 to DSBs. Mechanistically, DIGA requires MRE11/CtIP and EXO1, factors that promote resection and hyper-resection at DSBs, and is dependent on the catalytic activity of the RAD51 recombinase. Furthermore, deletion or depletion of POLD3, POLD4, or RAD52, proteins involved in break-induced replication (BIR), significantly inhibited DIGA, suggesting that DIGA is mediated through a RAD51-dependent BIR-like process. DIGA induction was maximal if the cells encountered DSBs in early and mid S-phase, whereas cells competent for homologous recombination (in late S and G2) exhibited less DIGA induction. We propose that unshielded, hyper-resected ends of DSBs may nucleate a replication-like intermediate that enables cytotoxic long-range genomic DNA amplification mediated through BIR.

cancer biology↗

bioRxiv2023

Somatic structural variants driving distinct modes of oncogenesis in melanoma

The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histological and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the role of topologically associated domain (TAD) boundary altering SVs on cancer-related genes. Following our prior identification of double-stranded break repair deficiency in a subset of triple wild-type cutaneous melanoma, we identified MRE11 and NBN loss-of-function SVs in melanomas with this mutational signature. Experimental knockouts of MRE11 and NBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARPi in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact. Statement of SignificanceThe diversity of SVs in melanoma, and how they directly or indirectly impact oncogenesis, are incompletely known. Here we present analysis of melanoma SVs that reveal distinct global genomic properties and molecular drivers, some of which point to opportunities for further biological and therapeutic investigation.

cancer biology↗

bioRxiv2019

A virus hosted in malaria-infected blood protects against T cell-mediated inflammatory diseases by impairing DC function in a type I IFN-dependent manner

Co-infections shape the host immune status, thereby influencing the development of inflammatory diseases, which can result in detrimental or beneficial effects. For example, co-infections with concurrent Plasmodium species can alter malaria clinical evolution and malaria infection itself has the ability to modulate autoimmune reactions but, in both cases, the underlying mechanisms remain ill-defined.\n\nHere, we demonstrate that the protective effects of certain rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus co-hosted in malaria-parasitized blood. We show that live as well as extracts of blood parasitized by P. berghei K173 or P. yoelii 17X YM, confer full protection against Pb ANKA (PbA)-induced Experimental Cerebral Malaria (ECM) and MOG/CFA-induced experimental autoimmune encephalomyelitis (EAE), and that this is associated with a strong type I IFN signature. We detected the presence of a viral element, the RNA virus Lactate Dehydrogenase-elevating Virus (LDV), in the protective Plasmodium stabilates and we established that infection with LDV alone recapitulates the protective effects on ECM and EAE. In ECM, we further show that protection results from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and in their ability to produce the Th1-inducing IL-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, protection is achieved by IFN-I mediated blunting of IL-12 and IL-23, preventing the differentiation of IFN-{gamma}-, IL-17- and GM-CSF-producing encephalitogenic CD4+ T cells.\n\nThus, our results identify a virus that is co-hosted in several Plasmodium stabilates across the community and has major consequences on the host immune system. Moreover, our data emphasize the importance of considering concurrent infections for the understanding of autoimmunity and malaria-associated inflammatory complications.

immunology↗