A5088991349- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Integrated Circuits and Semiconductor Failure Analysis
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Toxin Mechanisms and Immunotoxins
- Genomics and Chromatin Dynamics
- Electrostatic Discharge in Electronics
- CRISPR and Genetic Engineering
- Cell death mechanisms and regulation
- Wnt/β-catenin signaling in development and cancer
- Calcium signaling and nucleotide metabolism
- Computational Drug Discovery Methods
- Plant Genetic and Mutation Studies
- Biosimilars and Bioanalytical Methods
- RNA Interference and Gene Delivery
- Receptor Mechanisms and Signaling
- Connective Tissue Growth Factor Research
- Erythrocyte Function and Pathophysiology
- RNA modifications and cancer
- Trace Elements in Health
- Antibiotic Resistance in Bacteria
- Pancreatic function and diabetes
- Polymer crystallization and properties
- Advanced biosensing and bioanalysis techniques
Université de Montréal
2016-2025
HEC Montréal
2022
Sidney Kimmel Cancer Center
2011-2016
Thomas Jefferson University
2007-2016
Montreal Clinical Research Institute
2001-2011
Gene Therapy Laboratory
2006
Poly(ADP-ribose) polymerase-1 (PARP-1) (ADP, adenosine diphosphate) has a modular domain architecture that couples DNA damage detection to poly(ADP-ribosyl)ation activity through poorly understood mechanism. Here, we report the crystal structure of double-strand break in complex with human PARP-1 domains essential for activation (Zn1, Zn3, WGR-CAT). engages as monomer, and interaction organizes into collapsed conformation can explain strong preference automodification. The Zn1, WGR...
Poly(ADP-ribose)polymerase 1 (PARP-1) is a key eukaryotic stress sensor that responds in seconds to DNA single-strand breaks (SSBs), the most frequent genomic damage. A burst of poly(ADP-ribose) synthesis initiates damage response, whereas PARP-1 inhibition kills BRCA-deficient tumor cells selectively, providing first anti-cancer therapy based on synthetic lethality. However, mechanism underlying PARP-1's function remained obscure; inherent dynamics SSBs and multi-domain architecture...
DNA death grip Poly(ADP-ribose) polymerase–1 (PARP-1) binds to breaks and recruits repair components. Cancer-killing PARP-1 inhibitor (PARPi) compounds all block the same catalytic site but exhibit vastly different efficacy. Zandarashvili et al. investigated molecular impact of PARPi binding (see Perspective by Slade Eustermann). Different molecules perturb allostery in diverse manners: Some drive promote release from DNA, others retention. These insights help explain efficacies clinic...
PARP-1, PARP-2 and PARP-3 are DNA-dependent PARPs that localize to DNA damage, synthesize poly(ADP-ribose) (PAR) covalently attached target proteins including themselves, thereby recruit repair factors breaks increase efficiency. have in common two C-terminal domains—Trp-Gly-Arg (WGR) catalytic (CAT). In contrast, the N-terminal region (NTR) of PARP-1 is over 500 residues includes four regulatory domains, whereas smaller NTRs (70 40 residues, respectively) unknown structural composition...
Poly(ADP-ribose) polymerase-1 (PARP-1) has two homologous zinc finger domains, Zn1 and Zn2, that bind to a variety of DNA structures stimulate poly(ADP-ribose) synthesis activity mediate PARP-1 interaction with chromatin. The structural basis for is unknown, which limits our understanding regulation involvement in repair transcription. Here, we have determined crystal the individual Zn2 domains complex double strand break, providing first views fingers bound DNA. Zn1-DNA Zn2-DNA establish...
PARP-1 cleaves NAD+ and transfers the resulting ADP-ribose moiety onto target proteins subsequent polymers of ADP-ribose. An allosteric network connects multi-domain detection DNA damage to catalytic domain structural changes that relieve autoinhibition; however, mechanism autoinhibition is undefined. Here, we show using non-hydrolyzable analog benzamide adenine dinucleotide (BAD) results from a selective block on binding. Following detection, BAD binding leads in dynamics at distant...
Abstract PARP-1 is rapidly recruited and activated by DNA double-strand breaks (DSBs). Upon activation, synthesizes a structurally complex polymer composed of ADP-ribose units that facilitates local chromatin relaxation the recruitment repair factors. Here, we identify function for in DSB resection. Remarkably, inhibition leads to hyperresected DSBs. We show loss hyperresection are associated with Ku, 53BP1 RIF1 resection inhibitors from break site. curtains analysis EXO1-mediated blocked...
Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme with multiple cellular functions, including DNA repair, transcriptional regulation, and cell signaling. PARP-1 has modular architecture six independent domains comprising the 113-kDa polypeptide. Two zinc finger at N terminus of bind to thereby activate catalytic domain situated C enzyme. The tight coupling binding activities critical regulation function; however, mechanism for coordinating these remains an unsolved...
PARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, is substantially more abundant cells than HPF1, challenging whether can pervasively modulate PARP1. Here, we show biochemically that efficiently output at sub-stoichiometric ratios matching their relative cellular abundances. rapidly associates/dissociates from multiple molecules, initiating before initiates on...
PARP1 and PARP2 detect DNA breaks, which activates their catalytic production of poly(ADP-ribose) that recruits repair factors contributes to PARP1/2 release from DNA. PARP inhibitors (PARPi) are used in cancer treatment target activity, interfering with increasing persistence on damage. In addition, certain PARPi exert allosteric effects increase retention However, no clinical exhibit this behavior toward PARP1. contrast, we show an effect retains breaks a manner depends communication...
Abstract DNA breaks recruit and activate PARP1/2, which deposit poly-ADP-ribose (PAR) to XRCC1-Ligase3 other repair factors promote repair. Clinical PARP inhibitors (PARPi) extend the lifetime of damage-induced PARP1/2 foci, referred as ‘trapping’. To understand molecular nature ‘trapping’ in cells, we employed quantitative live-cell imaging fluorescence recovery after photo-bleaching. Unexpectedly, found that PARP1 exchanges rapidly at damage sites even presence clinical PARPi, suggesting...
PARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of single-strand breaks by PARP-1's F1 and F2 domains via process further domain assembly activation the catalytic (CAT); synthesis attachment poly(ADP-ribose) (PAR) chains protein sidechains then signals for repair components. A component transmission signal HD subdomain CAT, which alone bridges between assembled DNA-binding active site ART CAT. Here we present study isolated CAT...
PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, recruits to sites DNA damage where domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent repair. inhibition promising new way selectively target cancers harboring repair deficiencies. However, current inhibitors other PARPs, raising questions about long-term off-target effects. Here, we propose strategy targets allosteric regulation as...