Chromosome instability induced by mutations in TAD anchors leads to tumors

Abstract

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 (CCXXXAGGGGG) 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.