DNA damage checkpoints balance a tradeoff between diploid- and polyploid-derived arrest failures DOI Creative Commons
Kotaro Fujimaki, Ashwini Jambhekar, Galit Lahav

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 16, 2025

The DNA damage checkpoint system ensures genomic integrity by preventing the division of damaged cells. This operates primarily through G1/S and G2/M checkpoints, which are susceptible to failure; how these checkpoints coordinate quantitatively ensure optimal cellular outcomes remains unclear. In this study, we exposed non-cancerous human cells exogenous used single-cell imaging monitor spontaneous arrest failure. We discovered that fail in two major paths, resulting types with distinct characteristics, including ploidy, nuclear morphology, micronuclei composition. Computational simulations experiments revealed strengthening one reduced mode failure but increased other, leading a critical tradeoff for optimizing total rates. Our findings suggest strengths minimizing error inherently suboptimal any single type, elucidating systemic cause instability tetraploid-like response damage. Arrest-failed result from routes, each typeThese differ size, ploidy compositionStrengthening reduces arrest-failure type increases otherTotal is minimized when type. Single-cell quantitative analyses computational reveal balances between reducing diploid damage-induced polyploid study suggests minimize failure, need be sub-optimal individual

Language: Английский

Understanding the complexity of p53 in a new era of tumor suppression DOI
Yanqing Liu, Zhenyi Su, Omid Tavana

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(6), P. 946 - 967

Published: May 9, 2024

Language: Английский

Citations

111
Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets DOI Open Access
Alvina I. Khamidullina, Yaroslav E. Abramenko, Alexandra V. Bruter

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1263 - 1263

Published: Jan. 19, 2024

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision replication for fast proliferation and increased genomic instability. To overcome the consequences improper control, malignant frequently inactivate parts their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other which help maintain fork stability (ATR-CHK1). This creates dependency remaining DDR pathways, vulnerability further destabilization synthetic lethality inhibitors with common oncogenic alterations such mutations TP53, RB1, ATM, amplifications MYC, CCNE1 others. The RS normally limited by coordination cell cycle, transcription replication. Inhibition WEE1 PKMYT1 kinases, prevent unscheduled mitosis entry, leads fragility under-replicated sites. Recent evidence also shows that inhibition Cyclin-dependent kinases (CDKs), CDK4/6, CDK2, CDK8/19 CDK12/13 can contribute through disruption repair control. Here, we review main causes in cancers well therapeutic targets—ATR, CHK1, PARP inhibitors.

Language: Английский

Citations

21
Comprehensive genomic characterization of early-stage bladder cancer DOI Creative Commons
Frederik Prip, Philippe Lamy, Sia V. Lindskrog

et al.

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Language: Английский

Citations

2
Transcription–Replication Conflicts as a Source of Genome Instability DOI Creative Commons

Liana Goehring,

Tony T. Huang, Duncan J. Smith

et al.

Annual Review of Genetics, Journal Year: 2023, Volume and Issue: 57(1), P. 157 - 179

Published: Aug. 8, 2023

Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously the same sequence. Conflicts between transcription (transcription–replication conflicts, or TRCs) are widespread in prokaryotes eukaryotes have capacity cause damage compromise complete, faithful of genome. This review will highlight recent studies investigating genomic locations TRCs mechanisms by which they may be prevented, mitigated, resolved. We address work from model organisms mammalian systems but predominantly focus multicellular owing additional complexities inherent coordination context cell type–specific gene expression higher-order chromatin organization.

Language: Английский

Citations

33
The crisscross between p53 and metabolism in cancer DOI Creative Commons
Youxiang Mao, Peng Jiang

Acta Biochimica et Biophysica Sinica, Journal Year: 2023, Volume and Issue: 55(6), P. 914 - 922

Published: June 1, 2023

As the guardian of genome, p53 is well known for its tumor suppressor function in humans, controlling cell proliferation, senescence, DNA repair and death cancer through transcriptional non-transcriptional activities. p53 most frequently mutated gene human cancer, but how mutation or depletion leads to tumorigenesis still remains poorly understood. Recently, there has been increasing evidence that plays a vital role regulating cellular metabolism as metabolic adaptation nutrient starvation. In contrast, mutant proteins, especially those harboring missense mutations, have completely different functions compared wild-type p53. this review, we briefly summarize what about mediating anabolic catabolic particular discuss recent findings describing metabolites regulate functions. To illustrate variability complexity metabolism, will also review differential regulation by

Language: Английский

Citations

24
Research progress on the pharmacological mechanism, in vivo metabolism and structural modification of Erianin DOI Open Access
Xin Wei, Jiajia Liu, Ziming Xu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 173, P. 116295 - 116295

Published: Feb. 23, 2024

Erianin is an important bibenzyl compound in dendrobium and has a wide spectrum of pharmacological properties. Since was discovered, abundant results have been achieved the vitro synthesis, structural modification, mechanism research. Researchers developed series simple efficient synthesis methods to improve shortcomings poor water solubility by replacing chemical structure or coating it nanomaterials. broad anti-tumor significant effects. In addition, also actions like immune regulation, anti-inflammatory, anti-angiogenesis. A comprehensive understanding metabolism, action pathways great value for utilization Erianin. Therefore, this review conducts relatively systematic look back at from above four aspects, give reference evolvement further appliance

Language: Английский

Citations

9
Whole-genome doubling in tissues and tumors DOI Creative Commons

Marc A. Vittoria,

Ryan J. Quinton,

Neil J. Ganem

et al.

Trends in Genetics, Journal Year: 2023, Volume and Issue: 39(12), P. 954 - 967

Published: Sept. 14, 2023

Language: Английский

Citations

20
An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress DOI Creative Commons
Taichi Igarashi, Marianne Mazevet, Takaaki Yasuhara

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 17, 2023

Abstract Activation of the KRAS oncogene is a source replication stress, but how this stress generated and it tolerated by cancer cells remain poorly understood. Here we show that induction G12V expression in untransformed triggers H3K27me3 HP1-associated chromatin compaction an RNA transcription dependent manner, resulting fork slowing cell death. Furthermore, elevated ATR necessary sufficient for tolerance -induced to expand stress-tolerant (RSTCs). PrimPol phosphorylated at Ser255, potential Chk1 substrate site, under promotes repriming maintain progression survival ATR/Chk1-dependent manner. However, ssDNA gaps are heterochromatin PrimPol-dependent repriming, leading genomic instability. These results reveal role ATR-PrimPol enabling precancerous survive KRAS-induced clonally with accumulation

Language: Английский

Citations

18
CDK4/6 activity is required during G 2 arrest to prevent stress-induced endoreplication DOI
Connor McKenney, Yovel Lendner, Adler Guerrero Zuniga

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6695)

Published: May 2, 2024

Cell cycle events are coordinated by cyclin-dependent kinases (CDKs) to ensure robust cell division. CDK4/6 and CDK2 regulate the growth 1 (G ) synthesis (S) phase transition of responding mitogen signaling, promoting E2F transcription inhibition anaphase-promoting complex. We found that this mechanism was still required in G 2 -arrested cells prevent exit after S phase. This revealed a role for maintaining state, challenging notion is irreversible do not require mitogens passing restriction point. Exit from occurred during ribotoxic stress actively mediated stress-activated protein kinases. Upon relief stress, significant fraction underwent second round DNA replication led whole-genome doubling.

Language: Английский

Citations

8
p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice DOI Creative Commons
Ross J. Hill, Nazareno Bona,

Job Smink

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 21, 2024

Abstract DNA repair deficiency can lead to segmental phenotypes in humans and mice, which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due different facing varying levels of damage or having reliance on specific pathways. However, we find that the cellular response determines tissue-specific outcomes. Here, use a mouse model human XPF-ERCC1 progeroid syndrome (XFE) caused by loss repair. We p53, central regulator damage, regulates tissue dysfunction Ercc1 -/- mice ways. show ablation p53 rescues hematopoietic stem cells, has no effect kidney, germ cell brain dysfunction, but exacerbates liver pathology polyploidisation. Mechanistically, led cell-cycle regulation liver, with reduced p21 expression. Eventually, p16 / Cdkn2a expression is induced, serving as fail-safe brake proliferation absence p53-p21 axis. Taken together, our data distinct functions play crucial role regulating phenotypes.

Language: Английский

Citations

7