Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1

Immortalized cells maintain telomere length through either a telomerase-dependent process or a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Homologous recombination is implicated in the ALT pathway in both yeast and human ALT cells. In ALT cells, two types of DNA...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2003-05, Vol.63 (10), p.2589-2595
Hauptverfasser: GUIKAI WU, XIANZHI JIANG, LEE, Wen-Hwa, CHEN, Phang-Lang
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XIANZHI JIANG
LEE, Wen-Hwa
CHEN, Phang-Lang
description Immortalized cells maintain telomere length through either a telomerase-dependent process or a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Homologous recombination is implicated in the ALT pathway in both yeast and human ALT cells. In ALT cells, two types of DNA double-strand break repair and homologous recombination factors, the Rad50/Mre11/NBS1 complex and Rad51/Rad52 along with replication factors (RPA) and telomere binding proteins (TRF1 and TRF2), are associated with the ALT-associated PML body (APB). DNA synthesis in late S-G(2) is associated with APBs, which contain telomeric DNA and, are therefore, potential sites for telomere length maintenance. Here, we show that the breast cancer susceptibility gene product, breast cancer susceptibility gene 1, and the human homologue of yeast Rap1, hRap1, are also associated with APBs specifically during late S-G(2) phase of the cell cycle. We additionally show that the localization of the double-strand break repair factors with APBs is distinct from their association with ionizing radiation-induced nuclear foci. To systematically explore the mechanism involved in the assembly of APBs, we examine the role of Nijmegen breakage syndrome 1 (NBS1) and TRF1 in this process, respectively. We demonstrated that NBS1 plays a key role in the assembly and/or recruitment of Rad50, Mre11, and breast cancer susceptibility gene 1, but not Rad51 or TRF1, to APBs. The NH(2) terminus of NBS1, specifically the BRCA1 COOH-terminal domain, is required for this activity. Although TRF1 interacts with NBS1 directly, it is dispensable for the association of either Rad50/Mre11/NBS1 or Rad51 with APBs. Perturbation of the interactions between NBS1/Mre11 and APBs correlates with reduced BrdUrd incorporation associated with APBs, consistent with decreased DNA synthesis at these sites. Taken together, these results support a model in which NBS1 has a vital role in the assembly of APBs, which function to maintain telomeres in human ALT cells.
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Homologous recombination is implicated in the ALT pathway in both yeast and human ALT cells. In ALT cells, two types of DNA double-strand break repair and homologous recombination factors, the Rad50/Mre11/NBS1 complex and Rad51/Rad52 along with replication factors (RPA) and telomere binding proteins (TRF1 and TRF2), are associated with the ALT-associated PML body (APB). DNA synthesis in late S-G(2) is associated with APBs, which contain telomeric DNA and, are therefore, potential sites for telomere length maintenance. Here, we show that the breast cancer susceptibility gene product, breast cancer susceptibility gene 1, and the human homologue of yeast Rap1, hRap1, are also associated with APBs specifically during late S-G(2) phase of the cell cycle. We additionally show that the localization of the double-strand break repair factors with APBs is distinct from their association with ionizing radiation-induced nuclear foci. To systematically explore the mechanism involved in the assembly of APBs, we examine the role of Nijmegen breakage syndrome 1 (NBS1) and TRF1 in this process, respectively. We demonstrated that NBS1 plays a key role in the assembly and/or recruitment of Rad50, Mre11, and breast cancer susceptibility gene 1, but not Rad51 or TRF1, to APBs. The NH(2) terminus of NBS1, specifically the BRCA1 COOH-terminal domain, is required for this activity. Although TRF1 interacts with NBS1 directly, it is dispensable for the association of either Rad50/Mre11/NBS1 or Rad51 with APBs. Perturbation of the interactions between NBS1/Mre11 and APBs correlates with reduced BrdUrd incorporation associated with APBs, consistent with decreased DNA synthesis at these sites. 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Homologous recombination is implicated in the ALT pathway in both yeast and human ALT cells. In ALT cells, two types of DNA double-strand break repair and homologous recombination factors, the Rad50/Mre11/NBS1 complex and Rad51/Rad52 along with replication factors (RPA) and telomere binding proteins (TRF1 and TRF2), are associated with the ALT-associated PML body (APB). DNA synthesis in late S-G(2) is associated with APBs, which contain telomeric DNA and, are therefore, potential sites for telomere length maintenance. Here, we show that the breast cancer susceptibility gene product, breast cancer susceptibility gene 1, and the human homologue of yeast Rap1, hRap1, are also associated with APBs specifically during late S-G(2) phase of the cell cycle. We additionally show that the localization of the double-strand break repair factors with APBs is distinct from their association with ionizing radiation-induced nuclear foci. To systematically explore the mechanism involved in the assembly of APBs, we examine the role of Nijmegen breakage syndrome 1 (NBS1) and TRF1 in this process, respectively. We demonstrated that NBS1 plays a key role in the assembly and/or recruitment of Rad50, Mre11, and breast cancer susceptibility gene 1, but not Rad51 or TRF1, to APBs. The NH(2) terminus of NBS1, specifically the BRCA1 COOH-terminal domain, is required for this activity. Although TRF1 interacts with NBS1 directly, it is dispensable for the association of either Rad50/Mre11/NBS1 or Rad51 with APBs. Perturbation of the interactions between NBS1/Mre11 and APBs correlates with reduced BrdUrd incorporation associated with APBs, consistent with decreased DNA synthesis at these sites. 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Biological markers</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>MRE11 Homologue Protein</subject><subject>Nuclear Proteins - metabolism</subject><subject>Osteosarcoma - metabolism</subject><subject>Osteosarcoma - ultrastructure</subject><subject>rap1 GTP-Binding Proteins - metabolism</subject><subject>Telomere - metabolism</subject><subject>Telomeric Repeat Binding Protein 1 - metabolism</subject><subject>Trf1 protein</subject><subject>Trf2 protein</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0EtPwzAMB_AKgdgYfAWUC9wq5dnHcSBe0gQHxrlyEmdkS9utaQ_99hQxxJGTbeln6y-fJHOmRJHmUqrTZE4pLVIlcz5LLmLcTqNiVJ0nM8ZzRXkh54lfxoi1DiNpHXFDY3rfNhDIcrVOIcbWeOjRkn3X1iOG1oy9NyTgsMPaA9Gt9RhJh4fBd1Pz6rc1brAhdx3CDjZI3sfGTrtI2GVy5iBEvDrWRfLx-LC-f05Xb08v98tV-iko71OnneI2U0KDLS0F6lBaARJKo5lGBxkFJSwzLmOm5AVVzlDDNTWo84IJsUhuf-5OmQ8Dxr6qfTQYAjTYDrHKBc8zNsn_ICs5z2XxffH6CAddo632na-hG6vfL07g5gggGgiug8b4-OfklDLLqfgCiOh-Hw</recordid><startdate>20030515</startdate><enddate>20030515</enddate><creator>GUIKAI WU</creator><creator>XIANZHI JIANG</creator><creator>LEE, Wen-Hwa</creator><creator>CHEN, Phang-Lang</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20030515</creationdate><title>Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1</title><author>GUIKAI WU ; XIANZHI JIANG ; LEE, Wen-Hwa ; CHEN, Phang-Lang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h302t-fbf52d653bad9d0a0fe4d3a4a9cb1befa60a53d1cf61c92805fc0c2b0ceb78133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Acid Anhydride Hydrolases</topic><topic>Biological and medical sciences</topic><topic>BRCA1 Protein - metabolism</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>DNA Repair</topic><topic>DNA Repair Enzymes</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - ultrastructure</topic><topic>Host-tumor relations. 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Biological markers</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>MRE11 Homologue Protein</topic><topic>Nuclear Proteins - metabolism</topic><topic>Osteosarcoma - metabolism</topic><topic>Osteosarcoma - ultrastructure</topic><topic>rap1 GTP-Binding Proteins - metabolism</topic><topic>Telomere - metabolism</topic><topic>Telomeric Repeat Binding Protein 1 - metabolism</topic><topic>Trf1 protein</topic><topic>Trf2 protein</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GUIKAI WU</creatorcontrib><creatorcontrib>XIANZHI JIANG</creatorcontrib><creatorcontrib>LEE, Wen-Hwa</creatorcontrib><creatorcontrib>CHEN, Phang-Lang</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GUIKAI WU</au><au>XIANZHI JIANG</au><au>LEE, Wen-Hwa</au><au>CHEN, Phang-Lang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2003-05-15</date><risdate>2003</risdate><volume>63</volume><issue>10</issue><spage>2589</spage><epage>2595</epage><pages>2589-2595</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Immortalized cells maintain telomere length through either a telomerase-dependent process or a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Homologous recombination is implicated in the ALT pathway in both yeast and human ALT cells. In ALT cells, two types of DNA double-strand break repair and homologous recombination factors, the Rad50/Mre11/NBS1 complex and Rad51/Rad52 along with replication factors (RPA) and telomere binding proteins (TRF1 and TRF2), are associated with the ALT-associated PML body (APB). DNA synthesis in late S-G(2) is associated with APBs, which contain telomeric DNA and, are therefore, potential sites for telomere length maintenance. Here, we show that the breast cancer susceptibility gene product, breast cancer susceptibility gene 1, and the human homologue of yeast Rap1, hRap1, are also associated with APBs specifically during late S-G(2) phase of the cell cycle. We additionally show that the localization of the double-strand break repair factors with APBs is distinct from their association with ionizing radiation-induced nuclear foci. To systematically explore the mechanism involved in the assembly of APBs, we examine the role of Nijmegen breakage syndrome 1 (NBS1) and TRF1 in this process, respectively. We demonstrated that NBS1 plays a key role in the assembly and/or recruitment of Rad50, Mre11, and breast cancer susceptibility gene 1, but not Rad51 or TRF1, to APBs. The NH(2) terminus of NBS1, specifically the BRCA1 COOH-terminal domain, is required for this activity. Although TRF1 interacts with NBS1 directly, it is dispensable for the association of either Rad50/Mre11/NBS1 or Rad51 with APBs. Perturbation of the interactions between NBS1/Mre11 and APBs correlates with reduced BrdUrd incorporation associated with APBs, consistent with decreased DNA synthesis at these sites. Taken together, these results support a model in which NBS1 has a vital role in the assembly of APBs, which function to maintain telomeres in human ALT cells.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>12750284</pmid><tpages>7</tpages></addata></record>
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subjects Acid Anhydride Hydrolases
Biological and medical sciences
BRCA1 Protein - metabolism
Cell Cycle Proteins - metabolism
DNA Repair
DNA Repair Enzymes
DNA-Binding Proteins - metabolism
Fibroblasts - metabolism
Fibroblasts - ultrastructure
Host-tumor relations. Immunology. Biological markers
Humans
Medical sciences
MRE11 Homologue Protein
Nuclear Proteins - metabolism
Osteosarcoma - metabolism
Osteosarcoma - ultrastructure
rap1 GTP-Binding Proteins - metabolism
Telomere - metabolism
Telomeric Repeat Binding Protein 1 - metabolism
Trf1 protein
Trf2 protein
Tumor Cells, Cultured
Tumors
title Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1
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