PARG inhibition induces nuclear aggregation of PARylated PARP1 DOI Creative Commons
Sateja Paradkar,

Julia Purcell,

Annie Cui

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 15, 2023

Abstract PARG inhibitors are currently under clinical development for the treatment of DNA repair-deficient cancers, however, their precise mechanism action is still unclear. Here we report that inhibition causes increased nuclear PARylated PARP1 limits chromatin binding in response to damage. This accumulates as aggregates at sites distinct from site damage, leading mis-localization PARP1. Additionally, these formed through PAR chains abrogating catalytic activity prevents formation. Finally, persist long-term and associated with cleaved cytoplasmic PARP1, a cell death hallmark, which ultimately leads non-apoptotic form death. Overall, our data uncovers novel inhibitor cytotoxicity, will inform ongoing studies.

Язык: Английский

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives DOI Creative Commons
Viola Previtali, Greta Bagnolini, Andrea Ciamarone

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(14), С. 11488 - 11521

Опубликована: Июль 2, 2024

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of growing number lethal targets led to significant expansion in the use lethality, far beyond poly(ADP-ribose) polymerase inhibitors used treat BRCA1/2-defective tumors. particular, molecular within DNA damage response have provided source that rapidly reached clinical trials. This Perspective focuses on most progress and their inhibitors, response, describing design associated therapeutic strategies. We will conclude by discussing current challenges new opportunities this promising field research, stimulate discussion medicinal chemistry community, allowing investigation reach its full potential.

Язык: Английский

Процитировано

16
DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications DOI
Yvette Drew, Frank T. Zenke, Nicola J. Curtin

и другие.

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 24(1), С. 19 - 39

Опубликована: Ноя. 12, 2024

Язык: Английский

Процитировано

11
Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts DOI
Xiaohui Lin, Dipika Gupta, Alina Vaitsiankova

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(20), С. 3916 - 3931.e7

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

5
A PARP2 active site helix melts to permit DNA damage-induced enzymatic activation DOI

Emily S Smith-Pillet,

Ramya Billur, Marie-France Langelier

и другие.

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites DOI Creative Commons
Xiaohui Lin,

Kay Sze Karina Leung,

Kaitlynn F. Wolfe

и другие.

Nucleic Acids Research, Год журнала: 2025, Номер 53(4)

Опубликована: Фев. 8, 2025

Abstract Poly-ADP-ribose polymerases 1 and 2 (PARP1 2) are critical sensors of DNA-strand breaks targets for cancer therapy. Upon DNA damage, PARP1 synthesize poly-ADP-ribose (PAR) chains on themselves other substrates, facilitating single-strand break repair by recruiting PAR-binding factors, including X-ray cross-complementing group (XRCC1) aprataxin polynucleotide kinase phosphatase-like factor (APLF). While diverse lesions activate PARP1, PARP2 is selectively activated 5′ phosphorylated nicks. They function independently compensate each other. Previous studies suggest that its PAR act upstream to recruit damage sites. Here, we report the scaffold protein XRCC1 mediates PARP1- PAR-dependent recruitment XRCC1-deficiency causes hyperactivation while attenuating micro-irradiation-induced foci. Mechanistically, BRCT1 domain binds PAR, BRCT2 interacts with catalytic enzymatic activity LIG3 BRCT via residues D575 Y576. This mode enrichment important certain proteins, such as APLF, but dispensable others, XRCC1–BRCT1 domain. These findings highlight distinct role in synthesis uncover unexpected hierarchical roles PARP2.

Язык: Английский

Процитировано

0
Caspase 3 and caspase 7 promote cytoprotective autophagy and the DNA damage response during non-lethal stress conditions in human breast cancer cells DOI Creative Commons
Gayathri Samarasekera,

Nancy E. Go,

Courtney Choutka

и другие.

PLoS Biology, Год журнала: 2025, Номер 23(3), С. e3003034 - e3003034

Опубликована: Фев. 21, 2025

Cell stress adaptation plays a key role in normal development and various diseases including cancer. Caspases are activated response to cell stress, growing evidence supports their function non-apoptotic cellular processes. A for effector caspases promoting stress-induced cytoprotective autophagy was demonstrated Drosophila, but has not been explored the context of human cells. We found functionally conserved caspase 3 (CASP3) 7 (CASP7) starvation or proteasome inhibition-induced breast cancer The loss CASP3 CASP7 resulted an increase PARP1 cleavage, reduction LC3B ATG7 transcript levels, H2AX phosphorylation, consistent with block DNA damage-induced pathways. Surprisingly, non-lethal conditions, underwent non-canonical processing at two calpain cleavage sites flanking exosite, resulting stable CASP7-p29/p30 fragments. Expression fragment(s) could rescue phosphorylation double knockout background. Strikingly, yet these phenotypes, exhibited synthetic lethality BRCA1 loss. These findings support through modulation reveal new therapeutic avenues investigation.

Язык: Английский

Процитировано

0
PARticular MARks: Histone ADP-ribosylation and the DNA Damage Response DOI

Cem Özdemir,

Laura R. Purkey,

Anthony Sanchez

и другие.

DNA repair, Год журнала: 2024, Номер 140, С. 103711 - 103711

Опубликована: Июнь 22, 2024

Язык: Английский

Процитировано

3
Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts DOI Open Access
Xiaohui Lin, Dipika Gupta, Alina Vaitsiankova

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 14, 2024

Summary PARP1&2 enzymatic inhibitors (PARPi) are promising cancer treatments. But recently, their use has been hindered by unexplained severe anemia and treatment-related leukemia. In addition to inhibition, PARPi also trap at DNA lesions. Here, we report that unlike Parp2 -/- mice, which develop normally, mice expressing catalytically-inactive (E534A, EA/EA ) succumb Tp53- Chk2 -dependent erythropoietic failure in utero , mirroring Lig1 mice. While damage mainly activates PARP1, demonstrate replication PARP2 robustly. is selectively recruited activated 5’-phosphorylated nicks (5’p-nicks) between Okazaki fragments, typically resolved Lig1. Inactive PARP2, but not its active form or absence, impedes Lig1- Lig3-mediated ligation, causing dose-dependent fork collapse, particularly harmful erythroblasts with ultra-fast forks. This PARylation-dependent structural function of 5’p-nicks explains the detrimental effects inhibition on erythropoiesis, revealing mechanism behind PARPi-induced leukemia, especially those TP53/CHK2 loss. Significance work shows hematological toxicities associated PARP stem from impaired PARP1 activity rather presence inactive protein. Mechanistically, these reflect a unique role during erythroblasts.

Язык: Английский

Процитировано

2
XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites DOI Open Access
Xiaohui Lin,

Kay Sze Karina Leung,

Kaitlynn F. Wolfe

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 17, 2024

Poly-ADP-ribose polymerases 1 and 2 (PARP1 PARP2) are crucial sensors of DNA-strand breaks emerging cancer therapy targets. Once activated by DNA breaks, PARP1 PARP2 generate poly-ADP-ribose (PAR) chains on themselves other substrates to promote single-strand break repair (SSBR). can be diverse lesions, whereas specifically recognizes 5' phosphorylated nicks. They independently provide mutual backup in the absence other. However, whether have synergistic functions damage response remains elusive. Here, we show that PAR generated recruit vicinity sites through scaffold protein XRCC1. Using quantitative live-cell imaging, found loss XRCC1 markedly reduces irradiation-induced foci PARP1-proficient cells. The central BRCT domain (BRCT1) binds chain, while C-terminal (BRCT2) interacts with catalytic PARP2, facilitating its localization near breaks. Together, these findings unveil a new function augmenting recruitment activation explain why PARP1, but not is aggregated hyperactivated XRCC1-deficient

Язык: Английский

Процитировано

1
Regulation of PARP1/2 and the tankyrases: emerging parallels DOI Creative Commons
Matthew Jessop,

Benjamin J. Broadway,

Katy Miller

и другие.

Biochemical Journal, Год журнала: 2024, Номер 481(17), С. 1097 - 1123

Опубликована: Авг. 23, 2024

ADP-ribosylation is a prominent and versatile post-translational modification, which regulates diverse set of cellular processes. Poly-ADP-ribose (PAR) synthesised by the poly-ADP-ribosyltransferases PARP1, PARP2, tankyrase (TNKS), 2 (TNKS2), all are linked to human disease. PARP1/2 inhibitors have entered clinic target cancers with deficiencies in DNA damage repair. Conversely, continued face obstacles on their way clinical use, largely owing our limited knowledge molecular impacts effector pathways, concerns around tolerability. Whilst detailed structure-function studies revealed comprehensive picture regulation, mechanistic understanding tankyrases lags behind, thereby appreciation consequences inhibition. Despite large differences architecture contexts, recent work has striking parallels regulatory principles that govern these enzymes. This includes low basal activity, activation intra- or inter-molecular assembly, negative feedback regulation auto-PARylation, allosteric communication. Here we compare point towards emerging open questions, whose pursuit will inform future drug development efforts.

Язык: Английский

Процитировано

1