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

Tuyen T Dang,Julio C Morales

doi:10.3390/cancers13133202

Tuyen T Dang, Julio C Morales

Open Access

https://doi.org/10.3390/cancers13133202

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Journal: Cancers	Publication Date: Jun 26, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: University of Oklahoma Health Sciences Center

Abstract

Simple SummaryCentromere 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.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.

Highlights

Chromosomal segregation is a fundamental process that occurs during every cell division
We find that one role of Centromere Protein I (CENP-I) in Homologous recombination (HR) repair is RNA:DNA hybrid resolution, as expression of RNaseH1 restores HR repair efficiency
We identified a role for CENP-I in DNA damage response and HR repair

Summary

Introduction

Chromosomal segregation is a fundamental process that occurs during every cell division. Accurate and efficient chromosomal segregation is essential for maintaining normal cellular homeostasis, as mistakes in this process often lead to diseased states such as cancer [1]. Mitotic cells are extremely sensitive to DNA damage, especially DNA doublestrand breaks (DSBs) [2]. DSBs can be introduced into mitotic cells through a variety of different methods. DSBs introduced into the genome through replication stress can oftentimes be carried over into mitosis [3]. It is estimated that 10–20 DSBs can bypass the G2/M checkpoint [4]. While the chromosomal condensation that occurs during mitosis in preparation for segregation is typically protective, if DNA damage is already present, this process can hinder DSB repair [5]

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