A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels and activates the DNA damage response DOI Creative Commons
Apurva T. Prabhakar, Claire D. James,

Aya H. Youssef

и другие.

mBio, Год журнала: 2024, Номер 15(6)

Опубликована: Май 9, 2024

ABSTRACT An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 BRD4 is required for plasmid segregation function. The E2-TopBP1 promotes increased mitotic protein levels in U2OS N/Tert-1 cells, as well foreskin keratinocytes immortalized by HPV16 (HFK + HPV16). SIRT1 deacetylation reduces stability here we demonstrate that acetylation occurs during mitosis a interacting-dependent manner, promoting stabilization. p300 mediates due to switching off function confirmed p53 on lysine 382, known target deacetylation. can complex with growing cells but unable do so interaction; also wild-type outside of mitosis. lysines 111 112 are highly conserved residues across all K111 hyper-acetylation mitosis, Topoisomerase 1 (Top1). We K112 ubiquitination proteasomal degradation CHK2, phosphorylation activation DNA damage response (DDR). results present new model which inactivates activates DDR. This novel mechanism DDR, requirement viral life cycle. IMPORTANCE Human papillomaviruses (HPVs) causative agents around 5% cancers. While there prophylactic vaccines will significantly alleviate HPV disease burden future generations, currently no anti-viral strategies available treatment To generate such reagents, must understand more about cycle, particular viral-host interactions. Here, describe generated interacting host controls deacetylase SIRT1. disrupts order enhance proteins. essential cycle represents therapeutic target.

Язык: Английский

Exploiting replication gaps for cancer therapy DOI Creative Commons
Ke Cong, Sharon B. Cantor

Molecular Cell, Год журнала: 2022, Номер 82(13), С. 2363 - 2369

Опубликована: Май 13, 2022

Язык: Английский

Процитировано

67
Mitotic tethering enables inheritance of shattered micronuclear chromosomes DOI
Prasad Trivedi,

Christopher D. Steele,

Franco K.C. Au

и другие.

Nature, Год журнала: 2023, Номер 618(7967), С. 1049 - 1056

Опубликована: Июнь 14, 2023

Язык: Английский

Процитировано

40
Boveri and beyond: Chromothripsis and genomic instability from mitotic errors DOI Creative Commons
Alice Mazzagatti, Justin L. Engel, Peter Ly

и другие.

Molecular Cell, Год журнала: 2023, Номер 84(1), С. 55 - 69

Опубликована: Ноя. 28, 2023

Язык: Английский

Процитировано

24
Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A DOI Creative Commons
Karolina Pavic, Nikhil Gupta, Judit Domènech Omella

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Фев. 28, 2023

Abstract The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting in cancer are poorly understood. Here, we report level details and structural of inhibition by an oncoprotein CIP2A. Upon direct binding to trimer, CIP2A displaces PP2A-A subunit thereby hijacks both B56α, catalytic PP2Ac form CIP2A-B56α-PP2Ac pseudotrimer. Further, competes with B56α substrate blocking LxxIxE-motif pocket on B56α. Relevant oncogenic activity across cancers, N-terminal head domain-mediated interaction stabilizes protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis domain blunted MYC expression MEK phosphorylation, abrogated triple-negative breast vivo growth. Collectively, discover unique multi-step hijack mute complex regulation mechanism resulting suppressor inhibition. results unfold determinant for CIP2A, potentially facilitating therapeutic modulation other diseases.

Язык: Английский

Процитировано

22
FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells DOI Creative Commons
Ke Cong, Nathan J. MacGilvary, Silviana Lee

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 23, 2024

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ helicase. Yet, how relates to PARP1 inhibition or trapping, which contribute PARPi toxicity, remains unclear. Here, we find hinges on S-phase activity, is reduced deficient cells as G-quadruplexes sequester MSH2. Additionally, loss FANCJ-MLH1 interaction diminishes activity; however, depleting MSH2 reinstates gaps. Indicating sequestered trapped are distinct, increases resistance susceptible trapping. However, with BRCA1 deficiency, mirrors inhibition, detrimental commonality being activity. These insights underline crucial role activity during replication emphasize importance understanding drug mechanisms for enhancing therapeutic response.

Язык: Английский

Процитировано

12
CIP2A induces PKM2 tetramer formation and oxidative phosphorylation in non-small cell lung cancer DOI Creative Commons
Lijun Liang,

Fuying Yang,

Di Wang

и другие.

Cell Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Фев. 6, 2024

Abstract Tumor cells are usually considered defective in mitochondrial respiration, but human non-small cell lung cancer (NSCLC) tumor tissues shown to have enhanced glucose oxidation relative adjacent benign lung. Here, we reported that oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) inhibited glycolysis and promoted oxidative metabolism NSCLC cells. CIP2A bound pyruvate kinase M2 (PKM2) induced the formation PKM2 tetramer, with serine 287 as a novel phosphorylation site essential for dimer-tetramer switching. redirected mitochondrion, leading upregulation Bcl2 via phosphorylating at threonine 69. Clinically, level was positively correlated phosphorylated S287. CIP2A-targeting compounds synergized suppressing proliferation vitro vivo. These results indicated facilitates by promoting tetrameric formation, targeting exhibits therapeutic potentials NSCLC.

Язык: Английский

Процитировано

11
Predictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions DOI Creative Commons
E. Schmid, Johannes C. Walter

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Protein-protein interactions (PPIs) are ubiquitous in biology, yet a comprehensive structural characterization of the PPIs underlying cellular processes is lacking. AlphaFold-Multimer (AF-M) has potential to fill this knowledge gap, but standard AF-M confidence metrics do not reliably separate relevant from an abundance false positive predictions. To address limitation, we used machine learning on curated datasets train structure prediction and omics-informed classifier (SPOC) that effectively separates true predictions PPIs, including proteome-wide screens. We applied SPOC all-by-all matrix nearly 300 human genome maintenance proteins, generating ∼40,000 can be viewed at predictomes.org, where users also score their own with SPOC. High-confidence discovered using our approach enable hypothesis generation maintenance. Our results provide framework for interpreting large-scale screens help lay foundation interactome.

Язык: Английский

Процитировано

1
The transcriptomic architecture of common cancers reflects synthetic lethal interactions DOI Creative Commons
Syed Haider, Rachel Brough, Santiago Madera

и другие.

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

To maintain cell fitness, deleterious genetic alterations are buffered by compensatory changes in additional genes. In cancer, buffering processes could be targeted synthetic lethality. However, despite the large-scale identification of lethal effects preclinical models, evidence that these operate clinically is limited. This impedes application approaches. By integrating molecular profiling data from >9,000 cancers with screens, we show transcriptomic tumor suppressor gene (TSG) loss hyperexpression partners a common phenomenon, extending to multiple TSGs and histotypes. Transcriptomic also notable phenocopy TSG loss, such as BRCAness cancers, where expression BRCA1/2 genes correlates clinical outcome. Synthetic exhibit represent more robust effects. These observations have implications for understanding how cells tolerate part explain architectures cancer provide insight into target selection. Tumor upregulate following loss. may new harnessed therapeutically.

Язык: Английский

Процитировано

1
Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies DOI Creative Commons
Colin Stok, Yannick P. Kok, Nathalie van den Tempel

и другие.

Nucleic Acids Research, Год журнала: 2021, Номер 49(8), С. 4239 - 4257

Опубликована: Март 5, 2021

Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to blocking agents, a phenotype collectively known as 'BRCAness'. BRCAness become dependent on alternative repair pathways that are error-prone introduce specific patterns of somatic across genome. The increasing availability next-generation sequencing data tumour samples has enabled identification distinct mutational signatures associated BRCAness. These reveal pathways, including Polymerase θ-mediated end-joining RAD52-mediated single strand annealing active BRCA1/2-deficient tumours, pointing towards potential therapeutic targets these tumours. Additionally, insight into consequences unrepaired lesions may also aid BRCA-like tumours lacking gene inactivation. This is clinically relevant, respond favourably treatment DNA-damaging PARP inhibitors or cisplatin, which been successfully used treat patients BRCA1/2-defective In this review, we aim provide origins landscape by exploring molecular biology represent actionable cells.

Язык: Английский

Процитировано

52
Guiding ATR and PARP inhibitor combinations with chemogenomic screens DOI Creative Commons
Michal Zimmermann,

Cynthia Bernier,

Beatrice Kaiser

и другие.

Cell Reports, Год журнала: 2022, Номер 40(2), С. 111081 - 111081

Опубликована: Июль 1, 2022

Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) poly(ADP-ribose) polymerase (PARPis) synergistically kill tumor cells through modulation complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this, we performed a genome-wide CRISPR-Cas9 screen to identify genetic alterations that hypersensitize combination the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations, or "alternative lengthening telomeres" telomere maintenance mechanism. We show PARPi combinations carrying these at doses sub-therapeutic as single agents. also demonstrate mechanism hypersensitivity H2-deficient cells, where observe an irreversible replication catastrophe, allowing us design highly efficacious tolerable vivo dosing schedule. present comprehensive dataset inform development experimental framework applicable other drug strategies.

Язык: Английский

Процитировано

37