Molecular mechanisms in governing genomic stability and tumor suppression by the SETD2 H3K36 methyltransferase

2022 ◽  
pp. 106155
Author(s):  
Ulysses Tsz Fung Lam ◽  
Ee Sin Chen
Keyword(s):  
Tumor Suppression ◽  
Molecular Mechanisms ◽  
Genomic Stability

scholarly journals COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Amila Suraweera ◽  
Neha S. Gandhi ◽  
Sam Beard ◽  
Joshua T. Burgess ◽  
Laura V. Croft ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Peptide Mapping ◽  
Genomic Stability ◽  
Double Strand Breaks ◽  
Histone H2a ◽  
Dna Double Strand Breaks ◽  
Critical Function ◽  
Strand Breaks ◽  
Break Site ◽  
Non Homologous End Joining

AbstractGenomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.

scholarly journals The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression

Cell Reports ◽  
2014 ◽  
Vol 8 (3) ◽  
pp. 807-817 ◽  
Author(s):  
Andy Castillo ◽  
Atanu Paul ◽  
Baohua Sun ◽  
Ting Hsiang Huang ◽  
Yucai Wang ◽  
...  
Keyword(s):  
Tumor Suppression ◽  
Genomic Stability ◽  
Interacting Protein

scholarly journals Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiangbing Meng ◽  
Jason Z. Gao ◽  
Sean Michael T. Gomendoza ◽  
John W. Li ◽  
Shujie Yang
Keyword(s):  
Cancer Progression ◽  
Tumor Suppression ◽  
Tumor Suppressor Genes ◽  
Mevalonate Pathway ◽  
Genomic Stability ◽  
Mitotic Catastrophe ◽  
P53 Mutations ◽  
Aberrant Expression ◽  
Induce Cell Death ◽  
Recent Advances

p53 is among the most frequently mutated tumor suppressor genes given its prevalence in >50% of all human cancers. One critical tumor suppression function of p53 is to regulate transcription of downstream genes and maintain genomic stability by inducing the G1/S checkpoint in response to DNA damage. Tumor cells lacking functional p53 are defective in the G1/S checkpoint and become highly dependent on the G2/M checkpoint to maintain genomic stability and are consequently vulnerable to Wee1 inhibitors, which override the cell cycle G2/M checkpoint and induce cell death through mitotic catastrophe. In addition to the lost tumor suppression function, many mutated p53 (Mutp53) proteins acquire gain-of-function (GOF) activities as oncogenes to promote cancer progression, which manifest through aberrant expression of p53. In cancer cells with GOF Mutp53, statins can induce CHIP-mediated degradation of Mutp53 within the mevalonate pathway by blocking the interaction between mutp53 and DNAJA1. Therefore, targeting critical downstream pathways of Mutp53 provides an alternative strategy for treating cancers expressing Mutp53. In this review, we summarize recent advances with Wee1 inhibitors, statins, and mevalonate pathway inhibitors in cancers with p53 mutations.

Molecular mechanisms of tumor suppression by LKB1

FEBS Letters ◽  
2010 ◽  
Vol 585 (7) ◽  
pp. 944-951 ◽  
Author(s):  
Kari Vaahtomeri ◽  
Tomi P. Mäkelä
Keyword(s):  
Tumor Suppression ◽  
Molecular Mechanisms

The common fragile site FRA16D gene product WWOX: roles in tumor suppression and genomic stability

2014 ◽  
Vol 71 (23) ◽  
pp. 4589-4599 ◽  
Author(s):  
Rami I. Aqeilan ◽  
Muhannad Abu-Remaileh ◽  
Mohammad Abu-Odeh
Keyword(s):  
Gene Product ◽  
Tumor Suppression ◽  
Fragile Site ◽  
Genomic Stability ◽  
Common Fragile Site ◽  
The Common

scholarly journals The caloric restriction fallacy, rodent diet aids and the tumor suppression theory of aging

2021 ◽  
Author(s):  
Alexander Wolf
Keyword(s):  
Life Span ◽  
Caloric Restriction ◽  
Tumor Suppression ◽  
Molecular Mechanisms ◽  
Mouse Strains ◽  
Control Group ◽  
Obese Mouse ◽  
Healthy Weight ◽  
Nicotinamide Mononucleotide ◽  
Theory Of Aging

Understanding the molecular mechanisms of normal aging is a prerequisite to significantly increase human health span. Caloric restriction (CR), which delays aging in most animal models, serves as a yardstick to evaluate interventions extending life span. However, mice given unlimited access to food suffer severe obesity and benefits from CR might be through reducing obesity-associated mortality. Health gains from CR depend on the control mice being gluttonous enough and less obese mouse strains benefit far less from CR. Most pharmacologic interventions reported to mimic CR and increase life span in mice, including resveratrol, rapamycin, nicotinamide mononucleotide and metformin, also reduce mouse body weight. In primates, CR does not delay aging unless the control group is eating enough to suffer from obesity-related disease. Human survival peaks at a BMI achievable without CR. CR mimetics are just diet aids and CR should not be regarded as increasing longevity in healthy weight individuals. Instead, I propose the tumor suppression theory of aging: most phenotypes of aging are the consequence of tumor-suppressive cell senescence that has evolved to limit the tumorigenic potential of clonally expanding cells. A variant of the somatic mutation theory of aging, oncogenic mutations and clonal expansion (opposed to functional impairment) are postulated as the most relevant consequence of somatic mutations. Irreversible cell cycle arrest, accumulating senescent cells, the senescence-associated secretory phenotype and subsequent stem cell depletion eventually cause tissue dysfunction, loss of regeneration and the majority, if not most, phenotypes of aging.

scholarly journals The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression

Oncogene ◽  
2009 ◽  
Vol 29 (1) ◽  
pp. 1-10 ◽  
Author(s):  
R Wäsch ◽  
J A Robbins ◽  
F R Cross
Keyword(s):  
Tumor Suppression ◽  
Genomic Stability

Spontaneous modulation of a dynamic balance between bacterial genomic stability and mutability: roles and molecular mechanisms of the genetic switch

2014 ◽  
Vol 57 (3) ◽  
pp. 275-279 ◽  
Author(s):  
Le Tang ◽  
RuoWei Liu ◽  
Gang Jin ◽  
ErYing Zhao ◽  
GuiRong Liu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dynamic Balance ◽  
Genomic Stability ◽  
Genetic Switch

Transcription factor/DNA interactions visualized by electron spectroscopic imaging

1992 ◽  
Vol 50 (1) ◽  
pp. 450-451
Author(s):  
David P. Bazett-Jones ◽  
Mark L. Brown
Keyword(s):  
Transcription Factor ◽  
Dna Sequences ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Phosphorus Content ◽  
Spectroscopic Imaging ◽  
Electron Spectroscopic Imaging ◽  
Dna Backbone ◽  
Two Parameters ◽  
High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

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