Uncovering novel roles of tandem BRCA1 C‐terminal (BRCT) domains in DNA repair, genome stability and breast cancer (LB236)

Abstract

Pax transactivation domain‐interacting protein (PTIP) has an important role in preserving genomic stability and is essential for cell survival following DNA damage, although the precise mechanism is undefined. PTIP consists of three pairs of tandem BRCA1 C‐terminal (tBRCT) domains required for assembly into multiple protein complexes. Mutations that disrupt BRCT domain binding correlate with increased cancer rates. To determine its precise role in DNA repair, we profiled the expression of PTIP in breast cancer cell lines. Surprisingly, we’ve discovered a novel truncated isoform of PTIP, containing the last four C‐terminal BRCT domains, (PTIP‐delta). RNAi gene depletion studies reveal a post‐transcriptional origin of PTIP‐delta. Kinetic profiling of PTIP synthesis indicates that a significant portion of PTIP is processed to PTIP‐delta within hours of translation. Recombinant forms of this PTIP‐delta retain the ability to form nuclear repair foci. Biophysical characterization uncovers new oligomerization interfaces of higher order structures composed exclusively of PTIP‐delta. These studies indicate that PTIP‐delta participates in the formation of multiple structurally and stoichiometrically diverse complexes during DNA repair. These studies implicate new and unusual functional roles of PTIP in DNA repair, genome stability and breast cancer.Grant Funding Source: NCI K 22