Fig. 5: Model of SatIII regulation in tumorigenesis and chemoresistance.
From: Pericentromeric Satellite III transcripts induce etoposide resistance
Loss of BRCA1 results in an increased SatIII RNA expression through reduced ubiquitination of H2A and a relaxation of pericentromeric heterochromatin, reflected by a loss of H3K9me2 (left side, Zhu et al., 2018, Padeken et al.). SatIII RNA interacts with the BRCA1-associated protein network and destabilizes replication forks which in turn enhances DNA damage and genomic instability, ultimately promoting tumor growth. Etoposide also drives SatIII expression, but in this case, SatIII RNA facilitates the recruitment of TOP2A to TOP2ccs located at nSBs (our data). This leads to less DNA damage and subsequent downstream mechanisms that decrease genomic instability and therefore cells are more resistant against etoposide.
