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Homologous Chromosomes Make Contact at the Sites of Double-Strand Breaks in Genes in Somatic G0/G1-Phase Human Cells

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Homologous Chromosomes Make Contact at the Sites of Double-Strand Breaks in Genes in Somatic G0/G1-Phase Human Cells Homologous chromosomes make contact at the sites of double-strand breaks in genes in somatic G0/G1-phase human cells Manoj Gandhia,1, Viktoria N. Evdokimovaa,1, Karen T.Cuencob,c, Marina N. Nikiforovaa, Lindsey M. Kellya, James R. Stringerd, Christopher J. Bakkenistd,e, and Yuri E. Nikiforova,2 aDepartment of Pathology and Laboratory Medicine, University of Pittsburgh, Pittsburgh, PA 15213; bDepartment of Oral Biology, School of Dental Medicine and cDepartment of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219; dDepartment of Molecular Genetics, University of Cincinnati, Cincinnati, OH 45267; and eDepartments of Radiation Oncology and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213 Edited by James E. Cleaver, University of California, San Francisco, CA, and approved May 1, 2012 (received for review April 5, 2012) Double-strand DNA breaks (DSBs) are continuously induced in cells Results by endogenously generated free radicals and exogenous geno- Homologous Chromosomes Form Arm-Specific Contact Spontaneously toxic agents such as ionizing radiation. DSBs activate the kinase and After Exposure to Ionizing Radiation. We used four-color 3D- activity in sensor proteins such as ATM and DNA-PK, initiating FISH and confocal microscopy (11, 12) to analyze the pattern a complex DNA damage response that coordinates various DNA and frequency of interaction between homologous chromosomes repair pathways to restore genomic integrity. In this study, we in untreated and irradiated primary cultured human epithelial report the unexpected finding that homologous chromosomes thyroid cells and fibroblasts. Cells were highly enriched in G0/G1 contact each other at the sites of DSBs induced by either radiation by plating at high density in the absence of serum and other or the endonuclease I-PpoI in human somatic cells. Contact involves growth factors (84% of thyroid cells and 91% of fibroblasts were short segments of homologous chromosomes and is centered on in G0/G1 phase by FACS). For each chromosome, arm-specific a DSB in active genes but does not occur at I-PpoI sites in intergenic paints were used to visualize the p and q arm separately, and CELL BIOLOGY DNA. I-PpoI-induced contact between homologous genes is abro- a centromeric probe was used to monitor the location and du- gated by the transcriptional inhibitors actinomycin D and α-amanitin A fi plication of centromeres (Fig. 1 ). Contact between homologous and requires the kinase activity of ATM but not DNA-PK. Our nd- chromosomes was detected by using intensity-based image seg- ings provide documentation of a common transcription-related and mentation analysis (Fig. S1). S/G2-phase cells, which were ATM kinase-dependent mechanism that induces contact between identified by the presence of centromere duplication that occurs allelic regions of homologous chromosomes at sites of DSBs in in S phase (13), were excluded from further analysis. The accuracy human somatic cells. of the exclusion criterion was confirmed by combining PCNA (marker of S phase) or cyclin A (marker of S and G phase) (14) homologous chromosome interaction | homologous recombination 2 immunostaining and FISH analysis in selected experiments (Fig. 1 E and F). ouble-strand DNA breaks (DSBs) are continuously induced Arm-specific contact between homologous chromosomes was Din eukaryotic cells by the free radicals generated by endog- readily identified for all six chromosomes studied in epithelial enous metabolic processes and by exposure to environmental cells and all three chromosomes studied in fibroblasts. The genotoxic agents such as ionizing radiation (IR) and are con- common patterns of contact were between two homologous q – sidered to be the most dangerous DNA lesions (1 3). DSBs in- arms (Fig. 1B), between two homologous p arms (Fig. 1C), and duce a complex DNA damage response that activates DNA repair simultaneous contact between two p arms and two q arms of pathways and cell cycle checkpoints and induces chromatin homologous chromosomes, i.e., p:p and q:q contact (Fig. 1D and remodeling and apoptosis. ATM and DNA-PK, two phosphati- Fig. S2). dylinositol 3-kinase–like kinases, are primary mediators of the Analysis performed on primary thyroid epithelial cells from two DNA damage response to DSBs. Although ATM phosphorylates donors revealed that 15–26% (mean, 19%) of homologous chro- hundreds of substrates that are believed to regulate multiple mosomes had arm-specific contact in untreated cells (Fig. 1G). DNA repair pathways including DSB repair by homologous Fifteen minutes after exposure to 5-Gy IR, the frequency of arm- recombination (HR) (4, 5), DNA-PK primarily regulates a limited specific contact between homologous chromosomes doubled to group of effectors that mediate DSB repair by nonhomologous 28–45% (mean, 38%). Similar findings were observed in un- end-joining (NHEJ) (3, 6). Misrepair of DSBs can result in the treated and irradiated human fibroblasts (Fig. 1H). The frequency intrachromosomal and interchromosomal rearrangements that of contact between homologous chromosomes was ∼20-fold generate oncogenic gene fusions. Previously, we (7, 8) and others lower than the predicted frequency of DSBs induced by 5 Gy of IR (9, 10) have shown that cancer-specific chromosomal rear- (150–200 DSBs per cell; 6–8 DSBs per average-size chromo- rangements commonly arise as a result of exchange between some), indicating that if contact is due to formation of DSBs, chromosomal loci that are located in close spatial proximity at the time of DSB formation. While exploring the role of nuclear architecture and gene Author contributions: Y.E.N. and C.J.B. designed research; M.G., V.N.E., K.T., and L.M.K. topology in the generation of chromosomal rearrangements in performed research; Y.E.N., M.G., V.N.E., K.T., M.N.N., J.R.S., and C.J.B. analyzed data; and human somatic cells, we observed an unexpected finding that Y.E.N., M.G., V.N.E., M.N.N., J.R.S., and C.J.B. wrote the paper. homologous chromosomes frequently contact each other at the The authors declare no conflict of interest. sites of DSBs induced in G0/G1 cells by either IR or the re- This article is a PNAS Direct Submission. striction enzyme I-PpoI. Further characterization demonstrated 1M.G. and V.N.E. contributed equally to this work. that this contact between homologous chromosomes is initiated 2To whom correspondence should be addressed. E-mail: [email protected]. by DSBs in genes but not by DSBs in intergenic DNA, requires This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. active gene transcription, and depends on ATM kinase activity. 1073/pnas.1205759109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1205759109 PNAS Early Edition | 1of6 Downloaded by guest on September 30, 2021 cells (range 0.6–1.6%) for all chromosomes, whether cells were irradiated or not irradiated, which likely represents a background level of random contact. Homologous Chromosomes Form Contacts at the Sites of DSBs Induced by Homing Endonuclease I-PpoI in Gene Regions but Not Outside of Genes. To determine whether contact between the corresponding arms of homologous chromosomes was induced by a DSB, and to find whether it involves the same allelic region on both homologs, we induced DSBs at specific chromosomal sites by expressing the homing endonuclease I-PpoI (15, 16) in the TPC-1 human thyroid cancer cell line (17). To introduce the I-PpoI gene, cells were transduced with the HA-ER-I-PpoI ret- rovirus (gift of M. Kastan Duke Cancer Institute, Durham, NC) by using either a single infection or three sequential infections. To induce DSBs, the infected cells were treated with 4-hydrox- ytamoxifen (4-OHT), which causes I-PpoI to enter the nucleus (16, 18). I-PpoI induction for 6 h produced multiple γH2AX foci in ∼55% and ∼75% of cells after single and triple infections, respectively (Fig. 2A). Using site-specific DNA probes, we analyzed six chromosomal regions, all diploid in TPC-1 cells (Table S1). Two of the regions have an I-PpoI site located within genes (DAB1 on 1p and GRIP1 on 12q). Two other studied regions (2qIG and 5qIG) are intergenic loci containing an I-PpoI site. Two regions that lack an I-PpoI site (16pNC and 16qNC) were also analyzed. Quantitative PCR (qPCR) analysis revealed that between 9 and 16% of the analyzed target sites were cut at 6 h after I-PpoI induction (Fig. 2B), as expected based on previous observations showing that in human cells I-PpoI cleaves approximately 10% of the 200–300 target sites (16, 18). FISH analysis with site-specific probes combined with cyclin A staining revealed that, in G0/G1-phase cells, I-PpoI cleavage in- duced contact between gene regions on homologous chromosomes, but did not induce contact between homologous intergenic regions or regions that do not contain an I-PpoI site (Fig. 2 C and D). For both genes (DAB1 and GRIP1), the proportion of cells showing contact at the I-PpoI site corresponded to the proportion of cells with expected cleavage at that site, estimated based on the known efficiency of cutting at each site and number of infected cells after single and triple infection. By contrast, the two intergenic regions containing an I-PpoI site exhibited no increase in allelic contact above the level observed in cells before I-PpoI entering the nucleus and in DNA regions lacking an I-PpoI site. Additionally, the frequency of contact between heterologous gene pairs, i.e., between DAB1 and GRIP1 genes, was low and unchanged when studied before (0.93 ± 0.24%) and after (0.90 ± 0.21%) DSB induction by I-PpoI. To confirm that contact between homologous genes is a gen- eral phenomenon and not restricted to specific chromosomes, we Fig.
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