@article{%a1.%Y_170,

title = {R-loops and impaired autophagy trigger cGAS-dependent inflammation via micronuclei formation in Senataxin-deficient cells},

author = {Zannini L and Cardano M and Liberi G and Buscemi G},

url = {https://link.springer.com/article/10.1007/s00018-024-05380-3},

doi = {10.1007/s00018-024-05380-3},

year  = {2024},

date = {2024-08-19},

journal = {Cellular and molecular life sciences},

volume = {81},

issue = {1},

pages = {339},

abstract = {Senataxin is an evolutionarily conserved DNA/RNA helicase, whose dysfunctions are linked to neurodegeneration and cancer. A main activity of this protein is the removal of R-loops, which are nucleic acid structures capable to promote DNA damage and replication stress. Here we found that Senataxin deficiency causes the release of damaged DNA into extranuclear bodies, called micronuclei, triggering the massive recruitment of cGAS, the apical sensor of the innate immunity pathway, and the downstream stimulation of interferon genes. Such cGAS-positive micronuclei are characterized by defective membrane envelope and are particularly abundant in cycling cells lacking Senataxin, but not after exposure to a DNA breaking agent or in absence of the tumor suppressor BRCA1 protein, a partner of Senataxin in R-loop removal. Micronuclei with a discontinuous membrane are normally cleared by autophagy, a process that we show is impaired in Senataxin-deficient cells. The formation of Senataxin-dependent inflamed micronuclei is promoted by the persistence of nuclear R-loops stimulated by the DSIF transcription elongation complex and the engagement of EXO1 nuclease activity on nuclear DNA. Coherently, high levels of EXO1 result in poor prognosis in a subset of tumors lacking Senataxin expression. Hence, R-loop homeostasis impairment, together with autophagy failure and unscheduled EXO1 activity, elicits innate immune response through micronuclei formation in cells lacking Senataxin.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_68,

title = {Sex specific regulation of TSPY-Like 2 in the DNA damage response of cancer cells},

author = {Cardano M and Magni M and Alfieri R and Chan SY and Sabbioneda S and Buscemi G and Zannini L},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015022/},

doi = {10.1038/s41419-023-05722-2},

year  = {2023},

date = {2023-03-01},

journal = {Cell death and disease},

volume = {14},

issue = {3},

pages = {197},

abstract = {Females have a lower probability to develop somatic cancers and a better response to chemotherapy than males. However, the reasons for these differences are still not well understood. The X-linked gene TSPY-Like 2 (TSPYL2) encodes for a putative tumor suppressor protein involved in cell cycle regulation and DNA damage response (DDR) pathways. Here, we demonstrate that in unstressed conditions TSPYL2 is maintained at low levels by MDM2-dependent ubiquitination and proteasome degradation. Upon genotoxic stress, E2F1 promotes TSPYL2 expression and protein accumulation in non-transformed cell lines. Conversely, in cancer cells, TSPYL2 accumulates only in females or in those male cancer cells that lost the Y-chromosome during the oncogenic process. Hence, we demonstrate that while TSPYL2 mRNA is induced in all the tested tumor cell lines after DNA damage, TSPYL2 protein stability is increased only in female cancer cells. Indeed, we found that TSPYL2 accumulation, in male cancer cells, is prevented by the Y-encoded protein SRY, which modulates MDM2 protein levels. In addition, we demonstrated that TSPYL2 accumulation is required to sustain cell growth arrest after DNA damage, possibly contributing to protect normal and female cancer cells from tumor progression. Accordingly, TSPYL2 has been found more frequently mutated in female-specific cancers. These findings demonstrate for the first time a sex-specific regulation of TSPYL2 in the DDR of cancer cells and confirm the existence of sexual dimorphism in DNA surveillance pathways.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybq,

title = {Sex disparities in DNA damage response pathways: Novel determinants in cancer formation and therapy},

author = {Cardano M and Buscemi G and Zannini L},

url = {https://www.sciencedirect.com/science/article/pii/S2589004222001456?via%3Dihub},

doi = {10.1016/j.isci.2022.103875},

year  = {2022},

date = {2022-05-30},

journal = {iScience},

volume = {25},

issue = {3},

pages = {103875},

abstract = {Cancer incidence and survival are different between men and women. Indeed, females have a lesser risk and a better prognosis than males in many tumors unrelated to reproductive functions. Although the reasons for these disparities are still unknown, they constitute an important starting point for the development of personalized cancer therapies. One of the mechanisms that fuels carcinogenesis is the accumulation of defects in DNA damage response (DDR) pathways, a complex signaling cascade that senses DNA lesions and, depending on the severity, coordinates transient cell-cycle arrest, DNA replication, repair, apoptosis, and senescence, preventing genomic instability and cancer. Recently, evidence of sexual dimorphisms is emerging in these pathways, therefore providing new opportunities for precision medicine. Here, we will discuss current knowledge about sexual disparities in the DDR, their role in tumorigenesis and cancer progression, and the importance of considering sex contribution in both research and cancer therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_474,

title = {Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality. },

author = {Sanese P and Fasano C and Buscemi G and Bottino C and Corbetta S and Fabini E and Silvestri V and Valentini V and Disciglio V and Forte G and Lepore Signorile M and De Marco K and Bertora S and Grossi V and Guven U and Porta N and Di Maio V and Manoni E and Giannelli G and Bartolini M and {Del Rio A} and Caretti G and Ottini L and Simone C},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648160/},

doi = {10.1016/j.isci.2020.101604},

year  = {2020},

date = {2020-01-01},

journal = {iScience},

volume = {23},

number = {10},

pages = {101604},

abstract = {SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_79,

title = {TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage.},

author = {Magni M and Buscemi G and Maita L and Peng L and Chan SY and Montecucco A and Delia D and Zannini L},

url = {https://www.nature.com/articles/s41418-018-0168-6},

doi = {10.1038/s41418-018-0168-6},

year  = {2019},

date = {2019-03-06},

journal = {Cell death and differentiation},

volume = {26},

number = {5},

pages = {918-931},

abstract = {Protein acetylation and deacetylation events are finely regulated by lysine-acetyl-transferases and lysine-deacetylases and constitute an important tool for the activation or inhibition of specific cellular pathways. One of the most important lysine-acetyl-transferases is p300, which is involved in the regulation of gene expression, cell growth, DNA repair, differentiation, apoptosis, and tumorigenesis. A well-known target of p300 is constituted by the tumor suppressor protein p53, which plays a critical role in the maintenance of genomic stability and whose activity is known to be controlled by post-translational modifications, among which acetylation. p300 activity toward p53 is negatively regulated by the NAD-dependent deacetylase SIRT1, which deacetylates p53 preventing its transcriptional activation and the induction of p53-dependent apoptosis. However, the mechanisms responsible for p53 regulation by p300 and SIRT1 are still poorly understood. Here we identify the nucleosome assembly protein TSPY-Like 2 (TSPYL2, also known as TSPX, DENTT, and CDA1) as a novel regulator of SIRT1 and p300 function. We demonstrate that, upon DNA damage, TSPYL2 inhibits SIRT1, disrupting its association with target proteins, and promotes p300 acetylation and activation, finally stimulating p53 acetylation and p53-dependent cell death. Indeed, in response to DNA damage, cells silenced for TSPYL2 were found to be defective in p53 activation and apoptosis induction and these events were shown to be dependent on SIRT1 and p300 function. Collectively, our results shed new light on the regulation of p53 acetylation and activation and reveal a novel TSPYL2 function with important implications in cancerogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_154,

title = {Cell cycle and apoptosis regulator 2 at the interface between DNA damage response and cell physiology},

author = {Magni M and Buscemi G and Zannini L},

url = {https://www.sciencedirect.com/science/article/pii/S1383574218300073?via%3Dihub},

doi = {10.1016/j.mrrev.2018.03.004},

year  = {2018},

date = {2018-02-14},

journal = {Mutation research - Reviews in Mutation Research},

volume = {776},

pages = {1-9},

abstract = {Cell cycle and apoptosis regulator 2 (CCAR2 or DBC1) is a human protein recently emerged as a novel and important player of the DNA damage response (DDR). Indeed, upon genotoxic stress, CCAR2, phosphorylated by the apical DDR kinases ATM and ATR, increases its binding to the NAD+-dependent histone deacetylase SIRT1 and inhibits SIRT1 activity. This event promotes the acetylation and activation of p53, a SIRT1 target, and the subsequent induction of p53 dependent apoptosis. In addition, CCAR2 influences DNA repair pathway choice and promotes the chromatin relaxation necessary for the repair of heterochromatic DNA lesions. However, besides DDR, CCAR2 is involved in several other cellular functions. Indeed, through the interaction with transcription factors, nuclear receptors, epigenetic modifiers and RNA polymerase II, CCAR2 regulates transcription and transcript elongation. Moreover, promoting Rev-erbα protein stability and repressing BMAL1 and CLOCK expression, it was reported to modulate the circadian rhythm. Through SIRT1 inhibition, CCAR2 is also involved in metabolism control and, suppressing RelB and p65 activities in the NFkB pathway, it restricts B cell proliferation and immunoglobulin production. Notably, CCAR2 expression is deregulated in several tumors and, compared to the non-neoplastic counterpart, it may be up- or down-regulated. Since its up-regulation in cancer patients is usually associated with poor prognosis and its depletion reduces cancer cell growth in vitro, CCAR2 was suggested to act as a tumor promoter. However, there is also evidence that CCAR2 functions as a tumor suppressor and therefore its role in cancer formation and progression is still unclear. In this review we discuss CCAR2 functions in the DDR and its multiple biological activities in unstressed cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}