A5084581630- DNA Repair Mechanisms
- PARP inhibition in cancer therapy
- Calcium signaling and nucleotide metabolism
- Toxin Mechanisms and Immunotoxins
- Microtubule and mitosis dynamics
- Fungal and yeast genetics research
- CRISPR and Genetic Engineering
- Cancer-related Molecular Pathways
- Cancer therapeutics and mechanisms
- SARS-CoV-2 and COVID-19 Research
- Carcinogens and Genotoxicity Assessment
- Phytochemicals and Medicinal Plants
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Biological Research and Disease Studies
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Selenium in Biological Systems
- Viral Infections and Immunology Research
- Cannabis and Cannabinoid Research
- Signaling Pathways in Disease
- Renal and related cancers
- Steroid Chemistry and Biochemistry
- Cytomegalovirus and herpesvirus research
- Organoselenium and organotellurium chemistry
- Information Science and Libraries
Universidade de São Paulo
2019-2025
Universidade Brasil
2024
Universidade Cidade de São Paulo
2024
Genomic (Brazil)
2023
St Vincents Institute of Medical Research
2011-2019
Ministry of Education
2016-2017
University of Sussex
2016-2017
Coordenação de Aperfeicoamento de Pessoal de Nível Superior
2016-2017
The University of Melbourne
2011-2016
St Vincent's Hospital
2011-2013
ADP‐ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage viral infection is involved intra‐ extracellular signaling, chromatin transcriptional regulation, protein biosynthesis, cell death. ADP‐ribosylation catalyzed ADP‐ribosyltransferases (ARTs), which transfer ADP‐ribose from NAD + onto substrates. The modification, occurs as mono‐ or poly‐ADP‐ribosylation, reversible due...
Abstract PARP3 is a member of the ADP-ribosyl transferase superfamily that we show accelerates repair chromosomal DNA single-strand breaks in avian DT40 cells. Two-dimensional nuclear magnetic resonance experiments reveal employs conserved DNA-binding interface to detect and stably bind accumulate at sites chromosome damage. preferentially binds activated by mononucleosomes containing nicked which target trans-ribosylation activity single-histone substrate. Although nicks naked stimulate...
Abstract DNA single‐strand breaks (SSBs) disrupt replication and induce chromosome breakage. However, whether SSBs breakage when present behind forks or ahead of is unclear. To address this question, we exploited an exquisite sensitivity SSB repair‐defective human cells lacking PARP activity XRCC1 to the thymidine analogue 5‐chloro‐2′‐deoxyuridine (CldU). We show that incubation with CldU in these results breakage, sister chromatid exchange, cytotoxicity by a mechanism depends on S phase...
The highly conserved DYNLL1 (LC8) protein was originally discovered as a light chain of the dynein motor complex, but is increasingly emerging sequence-specific regulator dimerization with hundreds targets and wide-ranging cellular functions. Despite its important roles, DYNLL1's own regulation remains poorly understood. Here we identify ASCIZ (ATMIN/ZNF822), an essential Zn(2+) finger dual roles in DNA base damage response developmental transcription factor, Dynll1 gene expression. levels...
Post-translational modification of proteins by ADP-ribosylation, catalysed poly (ADP-ribose) polymerases (PARPs) using NAD+ as a substrate, plays central roles in DNA damage signalling and repair, modulates range cellular cascades initiates programmed cell death parthanatos. Here, we present mechanistic aspects ADP-ribose modification, PARP activation the functions signalling, discuss how this knowledge is uncovering therapeutic avenues for treatment increasingly prevalent human diseases...
Recent work in The EMBO Journal describes a new hybrid post-translational modification of proteins, composed poly-ubiquitin chain that is attached to target protein via mono-ADP-ribose (MAR) moiety. This "MARUbylation" likely play important functions during interferon signalling, core component innate immunity.
This study presents a new approach for identifying myeloperoxidase (MPO) inhibitors with strong in vivo efficacy. By combining inhibitor-like rules and structure-based virtual screening, the pipeline achieved 70% success rate discovering diverse, nanomolar-potency reversible hypochlorous acid (HOCl) scavengers. Mechanistic analysis identified RL6 as genuine MPO inhibitor RL7 potent HOCl scavenger. Both compounds effectively suppressed production cells neutrophils, showing superior inhibition...
To date, there are limited options for severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus. As ADP-ribosylation events involved in regulating the life cycle of coronaviruses and inflammatory reactions host; we have, here, assessed repurposing registered PARP inhibitors treatment COVID-19.
The essential yeast kinases Mec1 and Rad53, or human ATR Chk1, are crucial for checkpoint responses to exogenous genotoxic agents, but why they also required DNA replication in unperturbed cells remains poorly understood. Here we report that even the absence of DNA-damaging rad53-4AQ mutant, lacking N-terminal phosphorylation site cluster, is synthetic lethal with a deletion RAD9 damage adaptor. This phenotype caused by an inability activate downstream kinase Dun1, which then leads reduced...
The cell cycle checkpoint kinases play central roles in the genome maintenance of eukaryotes. Activation yeast kinase Rad53 involves Rad9 or Mrc1 adaptor-mediated phospho-priming by Mec1 kinase, followed auto-activating phosphorylation within its activation loop. However, mechanisms which these adaptors regulate priming specific sites and how this then leads to remain poorly understood. Here we used quantitative mass spectrometry delineate stepwise events endogenous response S phase...
Glioblastoma (GBM) is a highly aggressive brain tumor associated with poor patient survival. The current standard treatment involves invasive surgery, radiotherapy, and chemotherapy employing temozolomide (TMZ). Resistance to TMZ is, however, major challenge. Previous work from our group has identified candidate genes linked resistance, including encoding translesion synthesis (TLS) DNA polymerases iota (Polɩ) kappa (Polκ). These specialized enzymes are known for bypassing lesions tolerating...
Regulated cell death by a non-apoptotic pathway known as parthanatos is increasingly recognised central player in pathological processes, including ischaemic tissue damage and neurodegenerative diseases. Parthanatos activated under conditions that induce high levels of DNA damage, leading to hyperactivation the sensor PARP1. While this strict dependence on PARP1 activation defining feature distinguishes it from other forms death, molecular events downstream remain poorly understood. In...
Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It classified into two types: type I, biallelic variants in ANAPC1 and juvenile cataracts, II, RECQL4, increased cancer risk no cataracts. We report on six Brazilian probands siblings of Swiss/Portuguese ancestry presenting severe short stature, widespread congenital ocular anomalies. Genomic functional analysis revealed compound heterozygosis for deep intronic...
Mutations in subunits of the cilia-specific cytoplasmic dynein-2 (CD2) complex cause short-rib thoracic dystrophy syndromes (SRTDs), characterized by impaired bone growth and life-threatening perinatal respiratory complications. Different SRTD mutations result varying disease severities. It remains unresolved whether this reflects extent retained hypomorphic protein functions or relative importance affected for activity CD2 holoenzyme. To define contribution LC8-type dynein light chain...
Protein adenosine diphosphate (ADP)-ribosylation is crucial for a proper immune response. Accordingly, viruses have evolved ADP-ribosyl hydrolases to remove these modifications, prominent example being the SARS-CoV-2 NSP3 macrodomain, "Mac1". Consequently, inhibitors are developed by testing large libraries of small molecule candidates, with considerable success. However, relatively underexplored angle in design pertains synthesis structural substrate mimics. Here, we present and biophysical...