For genes involved in tissue generation and homeostasis, RNA polymerase II (Pol II) tends to pause immediately downstream of their transcription start sites. Compared to de novo recruitment of Pol II, a preassembled and poised Pol II could be more conducive to rapid and synchronous transcriptional activation in response to various physiologic cues. However, virtually nothing is known about the biological significance of this highly conserved and prevalent phenomenon in transcriptional regulation of tissue generation and homeostasis.

The histone H3 variant, centromere protein A (CENP-A), also localizes to DNA at double-strand breaks (DSBs), implying involvement in responses to DNA damage. CENP-A is normally a constituent of centromere specific chromatin, which forms the foundation for assembly of the kinetochore, a proteinaceous structure comprising a number of conserved protein complexes, that serve as the interface between chromosomes and spindle microtubules.

Breast cancer (BC) has several distinct molecular subtypes, including estrogen receptor (ESR1) positive andtriple negative BC (TNBC). A significant proportion of ESR1-positive therapy sensitive-BCs (TS-BC) initiallyrespond to antiestrogens or aromatase inhibitors, but become therapy resistant-BCs (TR-BC) and progress toincurable metastases. Further, TNBC subtype has a more aggressive clinical course and lack targetedtherapies. Development of effective therapies for women with TR-BC and TNBCs represents the highest unmetneed.