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Abstract
The p16(INK4a) tumor suppressor gene is a frequent target of epigenetic inactivation
in human cancers, which is an early event in breast carcinogenesis. We describe the
existence of a chromatin boundary upstream of the p16 gene that is lost when this
gene is aberrantly silenced. We show that the multifunctional protein CTCF associates
in the vicinity of this boundary and absence of binding strongly coincides with p16
silencing in multiple types of cancer cells. CTCF binding also correlates with RASSF1A
and CDH1 gene activation, and CTCF interaction is absent when these genes are methylated
and silenced. Interestingly, defective poly(ADP-ribosyl)ation of CTCF and dissociation
from the molecular chaperone Nucleolin occur in p16-silenced cells, abrogating its
proper function. Thus, destabilization of specific chromosomal boundaries through
aberrant crosstalk between CTCF, poly(ADP-ribosyl)ation, and DNA methylation may be
a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis
in numerous forms of human cancers.