Abstract
Malignant transformation of cells is associated with changes in gene
expression. Gross alterations in chromatin organization may be involved
in such gene dysregulation, as well as the involvement of specific
transcription factors. Specialized genomic DNA segments that exhibit
high affinity to the nuclear matrix in vitro have been designated
as matrix/scaffold attachment regions (MARs/SARs). MARs are postulated
to anchor chromatin onto the nuclear matrix, thereby organizing genomic
DNA into topologically distinct loop domains that are important in
replication and transcription. In support of this notion, MARs often
colocalize or exist in close proximity to regulatory sequences including
enhancers. Base unpairing regions (BURs) are typically 100-150 bp
regions within MARs, possess an intrinsic propensity to unwind under
negative superhelical strain, and are considered to be hallmark of
MARs. To investigate a potential mechanism that could lead to significant
alterations in gene expression in cancer cells, this review focuses
on a group of chromatin-associated proteins that specifically recognize
double stranded BURs. Several important proteins have been identified
from cancer cells as BUR-binding proteins, including poly (ADP-ribose)
polymerase (PARP-1), Ku autoantigen, SAF-A, HMG-I(Y), nucleolin and
p53. Many of these proteins are dramatically upregulated in malignancy
of the breast. Increase in the amount of these BUR-binding proteins,
some of which are known to interact with each other, may not only
provide an architectural core but also recruit functional multi-molecular
complexes at the base of chromatin loops to affect multiple distant
genes. Experimental strategies by which these proteins can be exploited
as carcinoma-specific diagnostic markers and as targets for antineoplastic
therapy are discussed.
- animals;
- antigens,
- b-lymphocytes,
- base
- biological
- cell
- chromatin,
- dna
- dna,
- dna-binding
- drug
- effects/metabolism
- effects/metabolism;
- expression
- gene
- genes,
- genetics;
- helicases;
- humans;
- markers;
- matrix,
- metabolism;
- neoplasm,
- neoplasms,
- neoplastic,
- nuclear
- nuclear;
- nucleus,
- p53,
- pathology/ultrasonography;
- pathology/ultrastructure;
- phosphoproteins,
- physiology;
- proteins,
- regulation,
- ribonucleoproteins,
- rna-binding
- sequence;
- ultrastructure;
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