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Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9454-9. doi: 10.1073/pnas.1205759109. Epub 2012 May 29.

Homologous chromosomes make contact at the sites of double-strand breaks in genes in somatic G0/G1-phase human cells.

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1
Department of Pathology and Laboratory Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Abstract

Double-strand DNA breaks (DSBs) are continuously induced in cells by endogenously generated free radicals and exogenous genotoxic agents such as ionizing radiation. DSBs activate the kinase activity in sensor proteins such as ATM and DNA-PK, initiating a complex DNA damage response that coordinates various DNA repair pathways to restore genomic integrity. In this study, we report the unexpected finding that homologous chromosomes contact each other at the sites of DSBs induced by either radiation or the endonuclease I-PpoI in human somatic cells. Contact involves short segments of homologous chromosomes and is centered on a DSB in active genes but does not occur at I-PpoI sites in intergenic DNA. I-PpoI-induced contact between homologous genes is abrogated by the transcriptional inhibitors actinomycin D and α-amanitin and requires the kinase activity of ATM but not DNA-PK. Our findings provide documentation of a common transcription-related and ATM kinase-dependent mechanism that induces contact between allelic regions of homologous chromosomes at sites of DSBs in human somatic cells.

PMID:
22645362
PMCID:
PMC3386068
DOI:
10.1073/pnas.1205759109
[Indexed for MEDLINE]
Free PMC Article
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