Genome instability from nuclear catastrophe and DNA damage

Mammel, Anna; Hatch, Emily M.

doi:10.1016/j.semcdb.2021.03.021

Cited by 22 publications

(15 citation statements)

References 77 publications

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“…4d). Confocal imaging started [16][17][18][19] hours after the mitotic shake-off and was performed as described above for about 24 h or until most of the cells of interest had divided and could be imaged in the generation 2.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, our group and others determined that structural abnormalities of the nucleus-micronuclei or chromosome bridges-can lead to a variety of simple and complex chromosomal rearrangements, including an extensive form of chromosome rearrangement called chromothripsis [12][13][14][15] . Chromothripsis enables rapid genome evolution of many cancers 16,17 . Although the role of nuclear abnormalities in self-amplifying genetic instability is now appreciated, other consequences of nuclear atypia have been little studied.…”

Section: Mainmentioning

confidence: 99%

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Transgenerational transcriptional heterogeneity from cytoplasmic chromatin

Papathanasiou

Mynhier

Liu

et al. 2022

Preprint

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Transcriptional heterogeneity from plasticity of the epigenetic state of chromatin is thought to contribute to tumor evolution, metastasis, and drug resistance. However, the mechanisms leading to nongenetic cell-to-cell variation in gene expression remain poorly understood. Here we demonstrate that heritable transcriptional changes can result from the formation of micronuclei, aberrations of the nucleus that are common in cancer. Micronuclei have fragile nuclear envelopes (NE) that are prone to spontaneous rupture, which exposes chromosomes to the cytoplasm and disrupts many nuclear activities. Using a combination of long-term live-cell imaging and same-cell, single-cell RNA sequencing (Look-Seq2), we identified significant reduction of gene expression in micronuclei, both before and after NE rupture. Furthermore, chromosomes in micronuclei fail to normally recover histone 3 lysine 27 acetylation, a critical step for the reestablishment of normal transcription after mitosis. These transcription and chromatin defects can persist into the next generation in a subset of cells, even after these chromosomes are incorporated into normal daughter nuclei. Moreover, persistent transcriptional repression is strongly associated with, and may be explained by, surprisingly long-lived DNA damage to these reincorporated chromosomes. Therefore, heritable alterations in transcription can originate from aberrations of nuclear architecture.

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Section: Methodsmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Transgenerational transcriptional heterogeneity from cytoplasmic chromatin

Papathanasiou

Mynhier

Liu

et al. 2022

Preprint

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show abstract

“…At 72 h, combination treatments induced synergistic levels of DNA damage, and a significant number of mitotic defects, associated with chromosome mis-segregation [61]. The destabilisation of replication forks via physical impediment, such as PARP-trapping, typically culminates in mitotic catastrophe, producing multinucleation or macronucleation, or micronucleation in the case of acentric or lagging chromosomes, as seen in this work [7,25,62].…”

Section: Discussionmentioning

confidence: 70%

Sesquiterpene Lactones Potentiate Olaparib-Induced DNA Damage in p53 Wildtype Cancer Cells

Osborne

Larrosa

Schmidt

2022

IJMS

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Despite notable advances in utilising PARP inhibitor monotherapy, many cancers are not PARP inhibitor-sensitive or develop treatment resistance. In this work, we show that the two structurally-related sesquiterpene lactones, a 2-bromobenzyloxy derivative of dehydrosantonin (BdS) and alantolactone (ATL) sensitise p53 wildtype, homologous recombination-proficient cancer cells to low-dose treatment with the PARP inhibitor, olaparib. Exposure to combination treatments of olaparib with BdS or ATL induces cell-cycle changes, chromosomal instability, as well as considerable increases in nuclear area. Mechanistically, we uncover that mitotic errors likely depend on oxidative stress elicited by the electrophilic lactone warheads and olaparib-mediated PARP-trapping, culminating in replication stress. Combination treatments exhibit moderately synergistic effects on cell survival, probably attenuated by a p53-mediated, protective cell-cycle arrest in the G2 cell-cycle phase. Indeed, using a WEE1 inhibitor, AZD1775, to inhibit the G2/M cell-cycle checkpoint further decreased cell survival. Around half of all cancers diagnosed retain p53 functionality, and this proportion could be expected to increase with improved diagnostic approaches in the clinic. Utilising sublethal oxidative stress to sensitise p53 wildtype, homologous recombination-proficient cancer cells to low-dose PARP-trapping could therefore serve as the basis for future research into the treatment of cancers currently refractory to PARP inhibition.

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“…HPV8 E6 attenuates cellular responses to micronuclei, promoting entry and completion of mitosis (Figure 6G). This is notable because completion of mitosis greatly increases the risk of chromothripsis (36, 39). If a second mitosis occurs, the chromatin trapped inside the micronucleus often becomes missegregated, resulting in further anaphase bridges and/or micronuclei (83, 84).…”

Section: Introductionmentioning

confidence: 99%

“…Micronuclear DNA is at risk of chromothripsis if the cell containing them completes mitosis (34, 36, 39). Because 8 E6 increases the frequency of micronuclei and promotes proliferation (Figure 3B and 6G), we hypothesized that 8 E6 caused chromothripsis.…”

Section: Introductionmentioning

confidence: 99%

Beta HPV8 E6 Induces Micronuclei Formation and Promotes Chromothripsis

Dacus

Stancic

Pollina

et al. 2022

Preprint

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Cutaneous beta genus human papillomaviruses (β-HPV) are suspected to promote the development of non-melanoma skin cancer (NMSC) by destabilizing the host genome. Multiple studies have established the genome destabilizing capacities of β-HPV proteins E6 and E7 as a co-factor with UV. However, the E6 protein from β-HPV8 (HPV8 E6) induces tumors in mice without UV exposure. Here, we examined a UV-independent mechanism of HPV8 E6-induced genome destabilization. We showed that HPV8 E6 reduced the abundance of anaphase bridge resolving helicase, Bloom syndrome protein (BLM). The diminished BLM was associated with increased segregation errors and micronuclei. These HPV8 E6-induced micronuclei had disordered micronuclear envelopes yet retained replication and transcription competence. HPV8 E6 decreased antiproliferative responses to micronuclei and time-lapse imaging revealed HPV8 E6 promoted cells with micronuclei to complete mitosis. Finally, whole genome sequencing revealed that HPV8 E6 induced chromothripsis in 9 chromosomes. These data provide insight into mechanisms by which HPV8 E6-induces genome instability independent of UV exposure.

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Genome instability from nuclear catastrophe and DNA damage

Cited by 22 publications

References 77 publications

Transgenerational transcriptional heterogeneity from cytoplasmic chromatin

Transgenerational transcriptional heterogeneity from cytoplasmic chromatin

Sesquiterpene Lactones Potentiate Olaparib-Induced DNA Damage in p53 Wildtype Cancer Cells

Beta HPV8 E6 Induces Micronuclei Formation and Promotes Chromothripsis

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