A5079648273- Cancer, Lipids, and Metabolism
- Diet and metabolism studies
- Cancer, Hypoxia, and Metabolism
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Cancer-related Molecular Pathways
- Carcinogens and Genotoxicity Assessment
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- DNA and Nucleic Acid Chemistry
- Metabolomics and Mass Spectrometry Studies
- Protein Degradation and Inhibitors
- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Advanced biosensing and bioanalysis techniques
- Fungal and yeast genetics research
- Connective tissue disorders research
- Bacterial Genetics and Biotechnology
- Peptidase Inhibition and Analysis
- Endoplasmic Reticulum Stress and Disease
- Telomeres, Telomerase, and Senescence
National Research Council
2024
Istituto di Genetica Molecolare
2015-2024
Czech Academy of Sciences, Institute of Molecular Genetics
2024
University of Sussex
2007-2011
University of Milan
2003-2006
After exposure to DNA-damaging agents that block the progress of replication fork, monoubiquitination proliferating cell nuclear antigen (PCNA) mediates switch from replicative translesion synthesis DNA polymerases. We show in human cells, PCNA is monoubiquitinated response methyl methanesulfonate and mitomycin C, as well UV light, albeit with different kinetics, but not bleomycin or camptothecin. Cyclobutane pyrimidine dimers are responsible for most ubiquitination events after...
The use of translesion synthesis (TLS) polymerases to bypass DNA lesions during replication constitutes an important mechanism restart blocked/stalled forks. Because TLS generally have low fidelity on undamaged DNA, the cell must regulate interaction with damaged versus maintain genome integrity. Saccharomyces cerevisiae checkpoint proteins Ddc1, Rad17, and Mec3 form a clamp-like structure (the 9-1-1 clamp) that has physical similarity homotrimeric sliding clamp proliferating nuclear...
The clinical phenotype in osteogenesis imperfecta (OI) is attributed to the dominant negative function of mutant type I collagen molecules extracellular matrix, by altering its structure and function. Intracellular retention has also been reported, but effect on cellular homeostasis less characterized. Using OI patient fibroblasts carrying mutations α1(I) α2(I) chains we demonstrate that retained are responsible for endoplasmic reticulum (ER) enlargement activation unfolded protein response...
Uncoordinated clashes between replication forks and transcription cause stress genome instability, which are hallmarks of cancer neurodegeneration. Here, we investigate the outcomes head-on replication-transcription collisions, using as a model system budding yeast mutants for helicase Sen1, ortholog human Senataxin. We found that RNA Polymerase II accumulates together with RNA:DNA hybrids at sites collisions. The fork both arrested during clash, leading to DNA damage and, in long run,...
Abstract Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation metabolites that reprogram tumor microenvironment (TME) and drive cancer could facilitate development precision nutrition approaches. Using Hi-MYC prostate mouse model, we demonstrated an obesogenic high-fat diet (HFD) rich in saturated fats accelerates c-MYC–driven invasive through...
DNA polymerase η (polη) belongs to the Y-family of polymerases and facilitates translesion synthesis past UV damage. We show that, after irradiation, polη becomes phosphorylated at Ser601 by ataxia-telangiectasia mutated Rad3-related (ATR) kinase. damage-induced phosphorylation depends on its physical interaction with Rad18 but is independent PCNA monoubiquitination. It requires ubiquitin-binding domain not PCNA-interacting motif. ATR-dependent necessary restore normal survival...
ABSTRACT Osteogenesis imperfecta (OI) types VII, VIII and IX, caused by recessive mutations in cartilage-associated protein (CRTAP), prolyl-3-hydroxylase 1 (P3H1) cyclophilin B (PPIB), respectively, are characterized the synthesis of overmodified collagen. The genes encode for components endoplasmic reticulum (ER) complex responsible 3-hydroxylation specific proline residues type I Our study dissects effects proteins on cellular homeostasis, using primary fibroblasts from seven OI patients....
Y-family DNA polymerases carry out translesion synthesis past damaged DNA. (pol) η and ι are usually uniformly distributed through the nucleus but accumulate in replication foci during S phase. DNA-damaging treatments result an increase phase cells containing polymerase foci. Using photobleaching techniques, we show that polη is highly mobile human fibroblasts. Even when localized foci, it only transiently immobilized. Although ubiquitination of proliferating cell nuclear antigen (PCNA) not...
Ribonucleotides (rNs) incorporated in the genome by DNA polymerases (Pols) are removed RNase H2. Cytidine and guanosine preferentially accumulate over other rNs. Here we show that human Pol η can incorporate cytidine monophosphate (rCMP) opposite guanine, 8-oxo-7,8-dihydroguanine, 8-methyl-2΄-deoxyguanosine a cisplatin intrastrand guanine crosslink (cis-PtGG), while it cannot bypass 3-methylcytidine or an abasic site with rNs as substrates. is also capable of synthesizing polyribonucleotide...
Abstract Females have a lower probability to develop somatic cancers and better response chemotherapy than males. However, the reasons for these differences are still not well understood. The X-linked gene TSPY-Like 2 (TSPYL2) encodes putative tumor suppressor protein involved in cell cycle regulation DNA damage (DDR) pathways. Here, we demonstrate that unstressed conditions TSPYL2 is maintained at low levels by MDM2-dependent ubiquitination proteasome degradation. Upon genotoxic stress,...
Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role regulation remodeling needs further clarification. This study examines how HDAC6 inactivation lysine acetyltransferase P300 stabilization subsequent effects on structure function cells.
DNA translesion synthesis (TLS) is a crucial damage tolerance pathway that oversees the completion of replication in presence damage. TLS polymerases are capable bypassing distorted template but they generally considered inaccurate and need to be tightly regulated. We have previously shown polη phosphorylated on Serine 601 after we demonstrated this modification important for efficient bypass. Here report also by CDK2, absence damage, cell cycle-dependent manner identify serine 687 as an...
Accurate DNA replication is critical for the maintenance of genome integrity and cellular survival. Cancer-associated alterations often involve key players damage-signalling cascade. Post-translational modifications play a fundamental role in coordinating repair central among them ubiquitylation. We show that E3 ligase UBR5 interacts with components fork, including translesion synthesis (TLS) polymerase polη. Depletion leads to problems, such as slower S-phase progression, resulting...
ABSTRACT The DNA damage response (DDR) is the signaling cascade that recognizes double-strand breaks (DSBs) and promotes their resolution via repair pathways of non-homologous end joining (NHEJ) or homologous recombination (HR). We others have shown DDR activation requires DROSHA; however, whether DROSHA exerts its functions by associating with sites, what controls recruitment, how influences remains poorly understood. Here, we show associates DSBs independently transcription. Neither H2AX,...