The DNA Damage Response and Inflammation in Cancer

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(7), P. 1521 - 1545

Published: April 7, 2023

Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting demise with unrepairable lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor progression resistance therapy. Indeed, signaling cancer has been consistently linked inhibition tumor-targeting immune responses. Here, we discuss complex interactions between inflammation context oncogenesis, progression, Accumulating preclinical clinical evidence indicates that intimately connected emission immunomodulatory signals malignant cells, part a program preserve organismal homeostasis. DDR-driven inflammation, however, have diametrically opposed effects on immunity. Understanding links may unlock novel immunotherapeutic paradigms treat cancer.

Language: Английский

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Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(6)

Published: Jan. 4, 2024

Aneuploidy, a deviation from the normal chromosome copy number, is common in human embryos and considered primary cause of implantation failure early pregnancy loss. Meiotic errors lead to uniformly abnormal karyotypes, while mitotic chromosomal mosaicism: presence cells with at least two different karyotypes within an embryo. Knowledge about mosaicism blastocysts mainly derives bulk DNA sequencing multicellular trophectoderm (TE) and/or inner cell mass (ICM) samples. However, this can only detect average net gain or loss above detection threshold 20-30%. To accurately assess mosaicism, we separated TE ICM 55 good quality surplus successfully applied single-cell whole genome (scKaryo-seq) on 1057 cells. Mosaicism involving numerical structural abnormalities was detected 82% embryos, where most affected less than 20% Structural abnormalities, potentially caused by replication stress damage, were observed 69% embryos. In conclusion, our findings indicated that prevalent good-quality blastocysts, these would likely be identified as current techniques used for preimplantation genetic testing aneuploidy (PGT-A).

Language: Английский

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Spatiotemporal view of malignant histogenesis and macroevolution via formation of polyploid giant cancer cells

Oncogene, Journal Year: 2023, Volume and Issue: 42(9), P. 665 - 678

Published: Jan. 3, 2023

Abstract To understand how malignant tumors develop, we tracked cell membrane, nuclear spindle, and cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade serous carcinoma organoids using long-term time-lapse imaging. Single underwent traditional mitosis to generate tissue with uniform size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, fusion, karyokinesis without cytokinesis. restitution fragmentation, micronuclei increase contents heterogeneity. At cellular level, development was associated forming transient intracellular cells, termed fecundity cells. The can be decellularized facilitate fusion synchronized other nuclei for subsequent replication. undergo several rounds entosis form complex structures, structures. multiple modes replication absence cytokinesis leads an nuclear-to-cytoplasmic (N/C) ratio reproduction, which is remarkably similar mode division pre-embryogenesis. Our data support that may represent a central regulator histogenesis, intratumoral heterogeneity, immune escape, macroevolution de-repression suppressed pre-embryogenic program somatic

Language: Английский

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Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: Oct. 2, 2023

Abstract Background The high incidence of aneuploidy in early human development, arising either from errors meiosis or postzygotic mitosis, is the primary cause pregnancy loss, miscarriage, and stillbirth following natural conception as well vitro fertilization (IVF). Preimplantation genetic testing for (PGT-A) has confirmed prevalence meiotic mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates transfer. However, only about half normally fertilized develop to blastocyst stage vitro, while others arrest at cleavage late morula stages. Methods To achieve a more complete view impacts aneuploidy, we applied low-coverage sequencing-based PGT-A large series ( n = 909) arrested trophectoderm biopsies. We then correlated observed with abnormalities first two divisions using time-lapse imaging 843). Results combined was strongly associated morphological grading, proportion ranging 20 90% highest lowest grades, respectively. In contrast, exceptionally (94%), dominated by affecting multiple chromosomes. turn, these were abnormal divisions, such 51% abnormally dividing possessed compared 23% embryos. Conclusions conclude combination drives development increasingly relies on embryonic gene expression stage.

Language: Английский

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Genetic mechanisms of fertilization failure and early embryonic arrest: a comprehensive review

Human Reproduction Update, Journal Year: 2023, Volume and Issue: 30(1), P. 48 - 80

Published: Sept. 27, 2023

Abstract BACKGROUND Infertility and pregnancy loss are longstanding problems. Successful fertilization high-quality embryos prerequisites for an ongoing pregnancy. Studies have proven that every stage in the human reproductive process is regulated by multiple genes any problem, at step, may lead to failure (FF) or early embryonic arrest (EEA). Doctors can diagnose pathogenic factors involved FF EEA using genetic methods. With progress development of new technologies, such as single-cell RNA analysis whole-exome sequencing, a approach has opened up us directly study germ cells development. These findings will help identify unique mechanism(s) leads order find potential treatments. OBJECTIVE AND RATIONALE The goal this review compile current knowledge related EEA, clarifying mechanisms providing clues clinical diagnosis treatment. SEARCH METHODS PubMed was used search relevant research articles reviews, primarily focusing on English-language publications from January 1978 June 2023. terms included failure, arrest, genetic, epigenetic, DNA methylation, chromosome, non-coding RNA, other keywords. Additional studies were identified searching reference lists. This focuses conducted humans. However, it also incorporates data animal models when applicable. results presented descriptively, individual quality not assessed. OUTCOMES A total 233 final review, 3925 records initially. provides overview process. mutations systematically reviewed, example, globozoospermia, oocyte activation maternal effect gene mutations, zygotic genome abnormalities, chromosome epigenetic abnormalities. Additionally, summarizes treatments different defects, offering insights WIDER IMPLICATIONS information provided facilitate more accurate molecular screening tools diagnosing infertility markers networks guide practice identifying appropriate interventions based specific mutations. For obvious FF, ICSI recommended instead IVF. case defects phospholipase C zeta1 (PLCZ1), actin-like7A (ACTL7A), actin-like 9 (ACTL9), IQ motif-containing N (IQCN), fail fertilize. We consider artificial technology with improve rate reduce monetary time costs. In future, fertility expected be improved restored interfering supplementing genes.

Language: Английский

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Prevalence of chromosomal alterations in first-trimester spontaneous pregnancy loss

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(12), P. 3233 - 3242

Published: Nov. 23, 2023

Pregnancy loss is often caused by chromosomal abnormalities of the conceptus. The prevalence these and allocation (ab)normal cells in embryonic placental lineages during intrauterine development remain elusive. In this study, we analyzed 1,745 spontaneous pregnancy losses found that roughly half (50.4%) products conception (POCs) were karyotypically abnormal, with maternal paternal age independently contributing to increased genomic aberration rate. We applied genome haplarithmisis a subset 94 normal parental POC karyotypes. Genotyping DNA as well extra-embryonic mesoderm chorionic villi DNA, representing trophoblastic tissues, enabled characterization landscape both lineages. Of losses, 35.1% had aberrations not previously detected karyotyping, increasing rate 67.8% extrapolation. contrast viable pregnancies where mosaic are restricted villi, such confined mosaicism, higher degree imbalances rather than villi. Our results stress importance scrutinizing full allelic architecture improve clinical management basic research devastating condition.

Language: Английский

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Replication stress as a driver of cellular senescence and aging

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: May 22, 2024

Abstract Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying the genome. While long considered a nexus for damage, role in aging is under-appreciated. The consequential promotion organismal phenotypes evidenced by an extensive list hereditary accelerated disorders marked molecular defects factors promote and operate uniquely response. Additionally, recent studies have revealed cellular pathways elicited align with designated hallmarks aging. Here we review advances demonstrating as ultimate driver senescence We discuss clinical implications intriguing links between including application senotherapeutic approaches context stress.

Language: Английский

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DNA replication in early mammalian embryos is patterned, predisposing lamina-associated regions to fragility

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

Published: June 19, 2024

Abstract DNA replication in differentiated cells follows a defined program, but when and how it is established during mammalian development not known. Here we show using single-cell sequencing, that late replicating regions are association with the B compartment nuclear lamina from first cell cycle after fertilization on both maternal paternal genomes. Late contain relative paucity of active origins few long genes low G/C content. In bovine mouse embryos, timing patterns prior to embryonic genome activation. Chromosome breaks, which form spontaneously embryos at sites concordant human preferentially locate regions. mice, enhanced fragility due sparsity dormant can be activated under conditions stress. This pattern predisposes neuronal genetic change separation soma germ lineages. Our studies segregation early among layers organization fertilization.

Language: Английский

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Embryonic genome instability upon DNA replication timing program emergence

Nature, Journal Year: 2024, Volume and Issue: 633(8030), P. 686 - 694

Published: Aug. 28, 2024

Faithful DNA replication is essential for genome integrity1–4. Under-replicated leads to defects in chromosome segregation, which are common during embryogenesis5–8. However, the regulation of remains poorly understood early mammalian embryos. Here we constructed a single-cell genome-wide atlas pre-implantation mouse embryos and identified an abrupt program switch accompanied by transient period genomic instability. In 1- 2-cell embryos, observed complete absence timing program, entire replicated gradually uniformly using extremely slow-moving forks. 4-cell somatic-cell-like commenced abruptly. fork speed was still slow, S phase extended, markers stress, damage repair increased. This followed increase break-type segregation errors specifically 4-to-8-cell division with breakpoints enriched late-replicating regions. These were rescued nucleoside supplementation, accelerated reduced stress. By 8-cell stage, forks gained speed, no longer extended aberrations decreased. Thus, instability exists normal development, preceded lacking coordination between replisome-level megabase-scale regulation, implicating link their stability. A reveals

Language: Английский

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Epigenome dynamics in early mammalian embryogenesis

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

Published: April 3, 2025

Language: Английский

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