Nuclear myosin/actin-motored contact between homologous chromosomes is initiated by ATM kinase and homology-directed repair proteins at double-strand DNA breaks to suppress chromosome rearrangements.

Viktoria N Evdokimova,Christopher J Bakkenist,Manoj Gandhi,Yuri E Nikiforov,Alyaksandr V Nikitski

doi:10.18632/oncotarget.24434

Viktoria N Evdokimova, Christopher J Bakkenist + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.24434

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Journal: Oncotarget	Publication Date: Feb 7, 2018
Citations: 16	License type: cc-by

Affiliation: University of Pittsburgh

Abstract

We provide evidence for a mechanism of DNA repair that requires nuclear myosin/actin-dependent contact between homologous chromosomes to prevent formation of chromosomal rearrangement in human cells. We recently showed that DNA double strand breaks (DSBs) induced by γ-rays or endonucleases cause ATM-dependent contact formation between homologous chromosomes at damaged sites of transcriptionally active chromatin in G0/G1-phase cells. Here, we report that the mechanism of contact generation between homologous chromosomes also requires homology-directed repair proteins, including BRCA1, RAD51 and RAD52, and nuclear myosin/actin-motors. Moreover, inhibition of ATM kinase or deficiency in nuclear actin polymerization causes carcinogenic RET/PTC chromosome rearrangements after DSBs induction in human cells. These data suggest that DSBs in transcriptionally active euchromatin in G0/G1-phase cells are repaired through a mechanism that requires contact formation between homologous chromosomes and that this mechanism is mediated by HDR proteins and nuclear myosin/actin motors.

Highlights

Mechanisms that ensure genome stability were essential for the origin of species and homeostasis in metazoans
We show that contact between homologous chromosomes after induction of DNA double strand break (DSB) in transcriptionally active chromatin in G0/G1-phase human cells requires homology-directed repair (HDR) but not non homologous end join (NHEJ) proteins
We show that contact between homologous chromosomes after induction of DSBs in transcriptionally www.impactjournals.com/oncotarget active chromatin in G0/G1-phase cells requires Homology-directed repair (HDR) proteins as well as nuclear myosin/actin motors

Summary

Introduction

Mechanisms that ensure genome stability were essential for the origin of species and homeostasis in metazoans. Non homologous end-joining (NHEJ) is an imperfect mechanism of repair wherein DSB ends are trimmed and the ends are ligated together leading to a loss of genetic material at the site of the break. Homologous recombination is a mechanism of repair that uses a sister chromatid as a template to correct a DSB without loss of genetic material. Since this canonical mechanism of homologous recombination requires the co-localization of sister chromatids, it is generally associated with DNA replication forks in S phase or with G2 phase cells. Observations that homologous chromosomes make contact after the induction of DSBs in G0/G1 cells, including mature thyroid cells [1, 2], led us hypothesize that a mechanism of homologous recombination that uses a homologous chromosome as a template may exist in cells when there is no sister chromatid template

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