Haploinsufficiency of an RB-E2F1-Condensin II complex leads to aberrant replication and aneuploidy.

Courtney H Coschi,Grant W Brown,Frederick A Dick,Vanessa Percy,Jianxin Wang,Alison L Martens,Ian Welch,Srikanth Talluri,David Gallo,Aren Marshall,Matthew J Cecchini,Charles A Ishak,Paul C Boutros

doi:10.1158/2159-8290.cd-14-0215

Abstract

Genome instability is a characteristic of malignant cells; however, evidence for its contribution to tumorigenesis has been enigmatic. In this study, we demonstrate that the retinoblastoma protein, E2F1, and Condensin II localize to discrete genomic locations including major satellite repeats at pericentromeres. In the absence of this complex, aberrant replication ensues followed by defective chromosome segregation in mitosis. Surprisingly, loss of even one copy of the retinoblastoma gene reduced recruitment of Condensin II to pericentromeres and caused this phenotype. Using cancer genome data and gene-targeted mice, we demonstrate that mutation of one copy of RB1 is associated with chromosome copy-number variation in cancer. Our study connects DNA replication and chromosome structure defects with aneuploidy through a dosage-sensitive complex at pericentromeric repeats. Genome instability is inherent to most cancers and is the basis for selective killing of cancer cells by genotoxic therapeutics. In this report, we demonstrate that instability can be caused by loss of a single allele of the retinoblastoma gene that prevents proper replication and condensation of pericentromeric chromosomal regions, leading to elevated levels of aneuploidy in cancer.

Highlights

Fidelity of DNA replication and cell division are critical processes in multicellular organisms
The pRB–E2F1–Condensin II complex identified in this study affects chromatin from S-phase to mitosis
Our findings suggest how replication and structural defects at pericentromeres may be connected to common chromosomal abnormalities in cancer

Summary

Introduction

Fidelity of DNA replication and cell division are critical processes in multicellular organisms. Unrepaired errors can be passed on to daughter cells and contribute to cancer [1]. Damaged DNA signals the cell cycle to arrest, and repair is undertaken before advancement into mitosis [2]. Recent evidence suggests exceptions to this rule, as damage observed before mitosis is transmitted through M-phase [3, 4]. These DNA lesions are often associated with replication stress [4, 5], and their ability to evade checkpoints suggests that their impact on genome instability and cancer may be significant [6].

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Conclusion