PAX-Interacting Protein 1 (PTIP) Promotes Apoptosis

PAX-interacting protein 1 (PTIP/PAXIP1) was discovered and initially characterized over three decades ago as a 1,056 amino acid-containing protein with six tandem BReast cancer C-Terminal (BRCT) repeats. PTIP functions broadly to catalyze histone methylation in DNA damage repair and within the hematopoietic lineage, to promote immunoglobulin variable region (variable, diversity, joining [VDJ]) and class switch recombination (CSR). In this report, we show that a fraction of PTIP is actively transported from the nucleus to mitochondria resulting in their aggregation, release of cytochrome c into the cytoplasm and cellular apoptosis. Deletion of an N-terminal glutamine-rich region (QR), mutation of a conserved threonine within BRCT3 and truncation of the C-terminal BRCT5 domain each significantly reduced apoptosis as well as its previously documented G2/M cell cycle function. This is the first report to identify a mitochondrial-based apoptotic mechanism employed by the PTIP transcription factor.