Loss of CENP-I Impairs Homologous Recombination and Sensitizes Cells to PARP1 Inhibition

SIMPLE SUMMARY: Centromere Protein I (CENP-I) is one of a family of cellular molecules that is essential for the separation of chromosomes during mitosis and mitotic progression. Interestingly, other CENP family proteins, such as CENP-A, have been shown to be involved in double-strand break repair. The goal of the current study was to determine the role of CENP-I in DNA repair and the DNA damage response. We found that loss of CENP-I results in increased double-strand break formation and chromosomal aberration. Consistent with these results we found that loss of CENP-I impairs homologous recombination and sensitizes cells to PARP1 inhibition. We also found that CENP-I expression is elevated in patients suffering from glioblastomas, suggesting that CENP-I may play a role in the progression for this disease. ABSTRACT: Centromere Protein I (CENP-I) is a member of the CENP-H/I/K complex. CENP-H/I/K is a major component of the inner kinetochore and aids in ensuring proper chromosomal segregation during mitosis. In addition to this chromosomal segregation function, CENP-I also plays a role in DNA double-strand break (DSB) repair. Loss of CENP-I leads to increased endogenous 53BP1 foci and R-loop formation, while reducing cellular survival after ionizing radiation and Niraparib, a PARP1 small molecule inhibitor, exposures. Cells lacking CENP-I display delayed 53BP1 foci regression, an indication that DSB repair is impaired. Additionally, loss of CENP-I impairs the homologous recombination DSB repair pathway, while having no effect on the non-homologous end-joining pathway. Interestingly, we find that RNaseH1 expression restores HR capacity in CENP-I deficient cells. Importantly, CENP-I expression is elevated in glioma tissue as compared to normal brain tissue. This elevated expression also correlates with poor overall patient survival. These data highlight the multi-functional role CENP-I plays in maintaining genetic, as well as chromosomal, stability and tumor survival.