Genome maintenance in the context of 4D chromatin condensation

Yu, Sonia; Yang, Fan; Shen, Wen Hong

doi:10.1007/s00018-016-2221-2

Cited by 14 publications

(19 citation statements)

References 180 publications

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“…The nucleosome functions as the first level of genomic impaction, where a chain of nucleosomes forming chromatin fibres (through the interaction of their tails with adjacent nucleosomes and other proteins) which assemble into higher order three-dimensional nuclear space in a hierarchical manner (forming loops and domains), ultimately assembling chromosomes [ 6 , 7 , 8 ] ( Figure 1 B–C).…”

Section: The Role Of Nucleosomes In Packaging Dnamentioning

confidence: 99%

Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer

McAnena

Brown

Kerin

2017

Cancers

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Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non-invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients.

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Section: The Role Of Nucleosomes In Packaging Dnamentioning

confidence: 99%

Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer

McAnena

Brown

Kerin

2017

Cancers

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“…S1B), many of which result in truncated mutants lacking Cterminal PTEN (5,10). Although plasma membrane-localized PTEN function is central to suppression of the PI3K/AKT pathway, recent studies have indicated that PTEN has PI3K/AKT-independent tumor-suppressor functions (11). Cells without functional PTEN display increased chromosome instability with a high frequency of DNA double-strand breaks (DSB), suggesting that its nuclear function acts as a caretaker of the genome (12,13).…”

Section: Introductionmentioning

confidence: 99%

Nuclear PTEN Localization Contributes to DNA Damage Response in Endometrial Adenocarcinoma and Could Have a Diagnostic Benefit for Therapeutic Management of the Disease

Mukherjee

Patterson

George

et al. 2018

Molecular Cancer Therapeutics

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Endometrial adenocarcinoma (EndoCA) is the most common gynecologic cancer type in the United States, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I tumors, which is often followed by radiotherapy, but most patients with advanced disease recur and have a poor prognosis, largely because the tumors become refractory to cytotoxic chemotherapies. PTEN, a commonly mutated tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway. Nuclear functions for PTEN have been proposed as well, but whether those affect EndoCA development, progression, or outcomes is not well understood. Using immunohistochemistry, nuclear PTEN expression was observed in approximately half of EndoCA patient tumors, independent of grade and cytoplasmic PTEN expression. Higher levels of the DNA damage response (DDR) marker, γH2AX, were observed by immunohistochemistry and immunofluorescence in human EndoCA tumor sections that were PTEN-negative, in murine EndoCA tissues that were genetically modified to be PTEN-null, and in Ishikawa EndoCA cells, which do not express endogenous PTEN. Overexpression of exogenous PTEN-WT or PTEN-NLS, a modified PTEN with an added nuclear localization signal, significantly improved both DDR and G-M transition in Ishikawa cells treated with a DNA-damaging agent. Whereas PARP inhibition with Olaparib was not as effective in Ishikawa cells expressing native or PTEN-NLS, inhibition with Talazoparib was not affected by PTEN overexpression. These results suggest that nuclear PTEN subcellular localization in human EndoCA could be diagnostic when considering DDR therapeutic intervention. .

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“…[1][2][3][4] PTEN targets phosphatidylinositol-3,4,5-triphosphate (PIP3) and antagonizes the major survival pathway regulated by phosphatidylinositol 3-kinase (PI3K)/Akt. [5][6][7] Increasing evidence indicates that nuclear PTEN has fundamental functions in maintenance of chromosomal stability, 2,[8][9][10][11][12][13][14] suggesting there are as yet unidentified mechanisms in the process of chromosome inheritance for which the function of PTEN is indispensable. It has been shown that PTEN plays an essential role in maintaining the structural integrity of individual chromosomes, 2 which supports recognition of PTEN as a guardian of the genome.…”

Section: Introductionmentioning

confidence: 99%

PTEN regulates PLK1 and controls chromosomal stability during cell division

Zhang

Hou

et al. 2016

Cell Cycle

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PTEN functions as a guardian of the genome through multiple mechanisms. We have previously established that PTEN maintains the structural integrity of chromosomes. In this report, we demonstrate a fundamental role of PTEN in controlling chromosome inheritance to prevent gross genomic alterations. Disruption of PTEN or depletion of PTEN protein phosphatase activity causes abnormal chromosome content, manifested by enlarged or polyploid nuclei. We further identify polo-like kinase 1 (PLK1) as a substrate of PTEN phosphatase. PTEN can physically associate with PLK1 and reduce PLK1 phosphorylation in a phosphatase-dependent manner. We show that PTEN deficiency leads to PLK1 phosphorylation and that a phospho-mimicking PLK1 mutant causes polyploidy, imitating functional deficiency of PTEN phosphatase. Inhibition of PLK1 activity or overexpression of a non-phosphorylatable PLK1 mutant reduces the polyploid cell population. These data reveal a new mechanism by which PTEN controls genomic stability during cell division.

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Genome maintenance in the context of 4D chromatin condensation

Cited by 14 publications

References 180 publications

Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer

Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer

Nuclear PTEN Localization Contributes to DNA Damage Response in Endometrial Adenocarcinoma and Could Have a Diagnostic Benefit for Therapeutic Management of the Disease

PTEN regulates PLK1 and controls chromosomal stability during cell division

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