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

Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency DOI Creative Commons
Ke Cong, Min Peng, Arne Nedergaard Kousholt

и другие.

Molecular Cell, Год журнала: 2021, Номер 81(15), С. 3128 - 3144.e7

Опубликована: Июль 2, 2021

Язык: Английский

Процитировано

239
CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition DOI Creative Commons

David Gallo,

Jordan T.F. Young,

Jimmy Fourtounis

и другие.

Nature, Год журнала: 2022, Номер 604(7907), С. 749 - 756

Опубликована: Апрель 20, 2022

Amplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling resistance to cytotoxic targeted therapies

Язык: Английский

Процитировано

131
DNA repair defects in cancer and therapeutic opportunities DOI Open Access

Jessica L. Hopkins,

Li Lan, Lee Zou

и другие.

Genes & Development, Год журнала: 2022, Номер 36(5-6), С. 278 - 293

Опубликована: Март 1, 2022

DNA repair and damage signaling pathways are critical for the maintenance of genomic stability. Defects contribute to tumorigenesis, but also render cancer cells vulnerable reliant on remaining activities. Here, we review major classes defects in cancer, instability that they give rise to, therapeutic strategies exploit resulting vulnerabilities. Furthermore, discuss impacts both targeted therapy immunotherapy, highlight emerging principles targeting therapy.

Язык: Английский

Процитировано

120
RHINO directs MMEJ to repair DNA breaks in mitosis DOI
Alessandra Brambati, Olivia Sacco, Sarina Y. Porcella

и другие.

Science, Год журнала: 2023, Номер 381(6658), С. 653 - 660

Опубликована: Июль 13, 2023

Nonhomologous end-joining (NHEJ) and homologous recombination (HR) are the primary pathways for repairing DNA double-strand breaks (DSBs) during interphase, whereas microhomology-mediated (MMEJ) has been regarded as a backup mechanism. Through CRISPR-Cas9-based synthetic lethal screens in cancer cells, we identified subunits of 9-1-1 complex (RAD9A-RAD1-HUS1) its interacting partner, RHINO, crucial MMEJ factors. We uncovered an unexpected function RHINO restricting to mitosis. accumulates M phase, undergoes Polo-like kinase 1 (PLK1) phosphorylation, interacts with polymerase θ (Polθ), enabling recruitment DSBs subsequent repair. Additionally, provide evidence that activity mitosis repairs persistent originate S phase. Our findings offer insights into relationship between genes

Язык: Английский

Процитировано

59
Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis DOI Creative Commons

Camille Gelot,

Marton Tibor Kovacs,

Simona Miron

и другие.

Nature, Год журнала: 2023, Номер 621(7978), С. 415 - 422

Опубликована: Сен. 6, 2023

Abstract DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple repair machineries tightly regulated throughout cell cycle 1 . In interphase, DSBs mainly repaired by non-homologous end joining and homologous recombination 2 However, these pathways completely inhibited in mitosis 3–5 , leaving fate mitotic unknown. Here we show polymerase theta 6 (Polθ) repairs thereby maintains contrast to other DSB factors, Polθ function is activated upon phosphorylation Polo-like kinase (PLK1). Phosphorylated recruited a direct interaction with BRCA1 C-terminal domains TOPBP1 DSBs, where it mediates broken ends. Loss leads defective resulting loss This further exacerbated deficient recombination, results death. Our identify as underlying cause synthetic lethality between recombination. Together, our findings reveal critical importance maintenance

Язык: Английский

Процитировано

58
CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer DOI Creative Commons
Takuya Tsujino, Tomoaki Takai, Kunihiko Hinohara

и другие.

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

Опубликована: Янв. 17, 2023

Abstract Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens BRCA1/2-proficient prostate cells and identify previously unknown whose loss has a profound impact on inhibitor response. Specifically, MMS22L deletion, frequently observed (up 14%) cancer, renders hypersensitive inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this is TP53 -dependent. Unexpectedly, CHEK2 confers resistance rather than sensitivity inhibition through increased expression BRCA2, target CHEK2-TP53-E2F7-mediated transcriptional repression. Combined ATR overcomes caused loss. Our findings may inform the use beyond BRCA1/2-deficient tumors support reevaluation current biomarkers cancer.

Язык: Английский

Процитировано

54
Mitotic clustering of pulverized chromosomes from micronuclei DOI Creative Commons
Yu-Fen Lin, Qing Hu, Alice Mazzagatti

и другие.

Nature, Год журнала: 2023, Номер 618(7967), С. 1041 - 1048

Опубликована: Май 10, 2023

Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis

Язык: Английский

Процитировано

49
Revolutionizing DNA repair research and cancer therapy with CRISPR–Cas screens DOI
Samah W. Awwad, Almudena Serrano-Benítez, John C. Thomas

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 24(7), С. 477 - 494

Опубликована: Фев. 13, 2023

Язык: Английский

Процитировано

48
Predictomes: A classifier-curated database of AlphaFold-modeled protein-protein interactions DOI Creative Commons
E. Schmid, Johannes C. Walter

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

Опубликована: Апрель 12, 2024

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

Язык: Английский

Процитировано

22
EXO1 protects BRCA1-deficient cells against toxic DNA lesions DOI Creative Commons
Bert van de Kooij, Anne Schreuder, Raphael Pavani

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(4), С. 659 - 674.e7

Опубликована: Янв. 23, 2024

Inactivating mutations in the BRCA1 and BRCA2 genes impair DNA double-strand break (DSB) repair by homologous recombination (HR), leading to chromosomal instability cancer. Importantly, BRCA1/2 deficiency also causes therapeutically targetable vulnerabilities. Here, we identify dependency on end resection factor EXO1 as a key vulnerability of BRCA1-deficient cells. generates poly(ADP-ribose)-decorated lesions during S phase that associate with unresolved DSBs genomic but not wild-type or BRCA2-deficient Our data indicate BRCA1/EXO1 double-deficient cells accumulate due impaired single-strand annealing (SSA) top their HR defect. In contrast, retain SSA activity absence hence tolerate loss. Consistent EXO1-mediated SSA, find BRCA1-mutated tumors show elevated expression increased SSA-associated scars compared BRCA1-proficient tumors. Overall, our findings uncover promising therapeutic target for

Язык: Английский

Процитировано

16