Molecular Lesions of Insulator CTCF and Its Paralogue CTCFL (BORIS) in Cancer: An Analysis from Published Genomic Studies

Voutsadakis, Ioannis A.

doi:10.3390/ht7040030

Cited by 10 publications

(7 citation statements)

References 50 publications

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“…These isoforms are following. CTCF gene has 13 exons with alternative splicing and produces at least 17 protein variants (Voutsadakis, 2018) with different immunogenic properties. Experimentalists usually use only one or few of the same commercially available antibodies.…”

Section: Structure Of Tad Anchorsmentioning

confidence: 99%

“…Experimentalists usually use only one or few of the same commercially available antibodies. CTCFL (BORIS) gene has 16 exons and 22-23 splice variants (Loukinov, 2018;Voutsadakis, 2018). In addition, posttranslational modifications add to diversity of variants of both proteins.…”

Section: Structure Of Tad Anchorsmentioning

confidence: 99%

“…At last these could be some disorders with CTCF-like protein (BORIS) which often occupies one of the two neighboring unidirectional tandem CTCF-G sites embracing Topo 2A/B site. BORIS has a great number of functional splice variants as well as CTCF itself has great number of functional splice variants (Voutsadakis, 2018). Shift in balance between variants of BORIS may also lead to formation of cancer stem cells (Loukinov, 2018).…”

Section: Structure Of Cancer Chromosomesmentioning

confidence: 99%

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Chromosome instability induced by mutations in TAD anchors leads to tumors

Luchnik

2021

GENOME INSTAB. DIS.

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In the light of recent data, a way is described between mutations in TAD anchors and stimulation of tumor growth driven by chromosome instability. At the end of this way every tumor sacrifices by a portion of its cells, dying necrotically, to stimulate remaining cells to proliferate. Necrosis (cell puncture and leakage of chemokine CXCL12) launches the mechanism of wound healing that stimulates cells to divide. Necrosis in cancer cells is induced by chromosome aberrations hindering anaphase cleavage furrow ingression and leading to membrane rupture. Inherited chromosome instability arises, because some of DNA loops (gene blocks, also called TADs) are torn off chromatid axes at their attachment points (anchors) because of mutations at some of these points. Namely, CTCF target sites (CCXXXAGG GGG ) at the basements of TAD loops acquire mutations in central Adenine and in 3-5 nucleotides just beyond the borders of this 11 bp sequence. The sequence itself is degenerate between different TADs mainly at the X nucleotides, rarely at some others. Interstitial satellite DNA (SAT) adjacent to TADs anchors begins to behave such as telomeric satellite DNA. This launches transcription of such erupted satellites not leaned against TADs and production of their DNA copies due to the action of TERT reverse transcriptase just like in telomeres and leads to insertion of telomere sequences into such SATs. Some sticky ends in satellites also add to chromosome instability.

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Section: Structure Of Tad Anchorsmentioning

confidence: 99%

Section: Structure Of Tad Anchorsmentioning

confidence: 99%

Section: Structure Of Cancer Chromosomesmentioning

confidence: 99%

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Chromosome instability induced by mutations in TAD anchors leads to tumors

Luchnik

2021

GENOME INSTAB. DIS.

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“…While it is clear that CTCF mutations are frequently identified in cancer, the degree to which such mutations alter CTCF’s binding capabilities and structure at the atomic level is not well understood [ 5 , 13 ]. Here, we use molecular dynamics (MD) simulations to further investigate the structural effect of eight different mutations identified in cancer patients [ 15 , 16 , 17 , 18 ]: R339Q, R342C, S354T, K365T, R377H/C, Q418R, and R448Q, located in ZFs 3 to 7. Overall, we find that all mutations except R342C and K365T reduce the stability of the DNA–CTCF complex due to the loss of hydrogen bonds or electrostatic interactions.…”

Section: Introductionmentioning

confidence: 99%

Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations

Mao

Chen

Portillo‐Ledesma

et al. 2023

IJMS

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In humans and other eukaryotes, DNA is condensed into chromatin fibers that are further wound into chromosomes. This organization allows regulatory elements in the genome, often distant from each other in the linear DNA, to interact and facilitate gene expression through regions known as topologically associating domains (TADs). CCCTC–binding factor (CTCF) is one of the major components of TAD formation and is responsible for recruiting a partner protein, cohesin, to perform loop extrusion and facilitate proper gene expression within TADs. Because single-residue CTCF mutations have been linked to the development of a variety of cancers in humans, we aim to better understand how these mutations affect the CTCF structure and its interaction with DNA. To this end, we compare all-atom molecular dynamics simulations of a wildtype CTCF–DNA complex to those of eight different cancer-linked CTCF mutant sequences. We find that most mutants have lower binding energies compared to the wildtype protein, leading to the formation of less stable complexes. Depending on the type and position of the mutation, this loss of stability can be attributed to major changes in the electrostatic potential, loss of hydrogen bonds between the CTCF and DNA, and/or destabilization of specific zinc fingers. Interestingly, certain mutations in specific fingers can affect the interaction with the DNA of other fingers, explaining why mere single mutations can impair CTCF function. Overall, these results shed mechanistic insights into experimental observations and further underscore CTCF’s importance in the regulation of chromatin architecture and gene expression.

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“…It is indicated that BORIS can act as a biomarker of breast cancer in women for Indian patients as well as breast cancer patients across the world. In breast cancer patients high levels of BORIS protein are detected in leukocytes, suggesting that BORIS can be used as an important biomarker for breast cancer progression [17] and is a male system-specific protein having the same 11-zinc finger structure as that of CTCF [18]. The expression of BORIS suppresses DNA damage and promotes resistance of cisplatin by enhancement of the mismatch repair system of cancer cells [19].…”

Section: Introductionmentioning

confidence: 99%

Association of mutation and expression of the brother of the regulator of imprinted sites (BORIS) gene with breast cancer progression

Akhtar,

Akhter,

Talat

et al. 2023

Oncotarget

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Introduction: The BORIS, 11 zinc-finger transcription factors, is a member of the cancer-testis antigen (CTA) family. It is mapped to chromosome number 20q13.2 and this region is genetically linked to the early onset of breast cancer. The current study analyzed the correlation between BORIS mutations and the expression of the protein in breast cancer cases. Materials and Methods: A population-based study including a total of 155 breast cancer tissue samples and an equal number of normal adjacent tissues from Indian female breast cancer patients was carried out. Mutations of the BORIS gene were detected by polymerase chain reaction-single standard confirmation polymorphisms (PCR-SSCP) and automated DNA sequencing and by immunohistochemistry for BORIS protein expression were performed. The observed findings were correlated with several clinicopathological parameters to find out the clinical relevance of associations. Results: Of all the cases 16.12% (25/155) showed mutations in the BORIS gene. The observed mutations present on codon 329 are missense, leading to Val> Ile (G>A) change on exon 5 of the BORIS gene. A significant association was observed between mutations of the BORIS gene and some clinicopathological features like nodal status (p = 0.013), estrogen receptor (ER) expression (p = 0.008), progesterone receptor (PR) expression (p = 0.039), clinical stage (p = 0.010) and menopausal status (p = 0.023). The protein expression analysis showed 20.64% (32/155) samples showing low or no expression (+), 34.19% (53/155) with moderate expression (++), and 45.17% (70/155) showing high expression (+++) of BORIS protein. A significant association was observed between the expression of BORIS protein and clinicopathological features like clinical stage (p = 0.013), nodal status (p = 0.049),

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Molecular Lesions of Insulator CTCF and Its Paralogue CTCFL (BORIS) in Cancer: An Analysis from Published Genomic Studies

Cited by 10 publications

References 50 publications

Chromosome instability induced by mutations in TAD anchors leads to tumors

Chromosome instability induced by mutations in TAD anchors leads to tumors

Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations

Association of mutation and expression of the brother of the regulator of imprinted sites (BORIS) gene with breast cancer progression

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