WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer
Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double‐strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the...
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| Veröffentlicht in: | BioEssays 2022-08, Vol.44 (8), p.e2200057-n/a |
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| description | Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double‐strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN‐BRCA2 genetic interaction under conditions of replication stress.
Suppression of WRN helicase's action to remodel stalled DNA replication forks in BRCA2‐deficient cancer cells causes genomic instability and cancer cell killing. Created with BioRender.com. |
| doi_str_mv | 10.1002/bies.202200057 |
| format | Article |
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Suppression of WRN helicase's action to remodel stalled DNA replication forks in BRCA2‐deficient cancer cells causes genomic instability and cancer cell killing. Created with BioRender.com.</description><subject>Aging</subject><subject>Aging, Premature</subject><subject>BRCA1 protein</subject><subject>BRCA2</subject><subject>BRCA2 protein</subject><subject>BRCA2 Protein - genetics</subject><subject>BRCA2 Protein - metabolism</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Chromosomal Instability</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA helicase</subject><subject>DNA Helicases - chemistry</subject><subject>DNA repair</subject><subject>DNA Replication</subject><subject>Exodeoxyribonucleases - genetics</subject><subject>Exodeoxyribonucleases - metabolism</subject><subject>Exonuclease</subject><subject>genetic disease</subject><subject>Genomic instability</subject><subject>Humans</subject><subject>Metabolism</subject><subject>Mutation</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - genetics</subject><subject>Ovarian cancer</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Replication</subject><subject>Replication forks</subject><subject>replication stress</subject><subject>synthetic lethality</subject><subject>Telomeres</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><subject>Werner Syndrome - genetics</subject><subject>Werner Syndrome - metabolism</subject><subject>Werner Syndrome Helicase - genetics</subject><subject>Werner Syndrome Helicase - metabolism</subject><subject>Werner's syndrome</subject><subject>WRN</subject><issn>0265-9247</issn><issn>1521-1878</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk1v1DAQhiMEokvhyhFZ4sJlF8cf-eCA1K4KVKoAFRBHy3YmG5ckTu2EKv-TH8SkW5aPC6ex5Od95x3NJMnTlG5SStlL4yBuGGWMUirze8kqlSxdp0Ve3E9WlGVyXTKRHyWPYrxCpMyYeJgccZnLVMh8lfz4evmeBIh2goh1aJ3Vo_M9qX34Fon13RB85yJUxMxEk9PL7QkjFdTOOujt_Ip8DFA5u2jiIiKNvyGub5xxtz6-RlUDi28EMjZ6JHEaBmwZsSPWTo9TAKJ3rt-R0bVjRAqI0a3uLSr8bRRsuaQguq-IbTCSj77TLXaKozaudeOMb2IXTXicPKh1G-HJXT1Ovrw5-7x9t7748PZ8e3KxtiIr8nVWasF0LoWpKjDSaqO5tVLqkuU5pBnPqBCyyoqMC8YLUYIFXtWMm7owhqf8OHm99x0m00FloR-DbtUQXKfDrLx26u-f3jVq57-rUrK8lBQNXtwZBH-NGxgVDmmhxdHBT1GxrEip4EW2oM__Qa_8FHocDynccbnERGqzp2zwMQaoD2FSqpaDUcvBqMPBoODZnyMc8F8XgkC5B25cC_N_7NTp-dmn3-Y_Aang0so</recordid><startdate>202208</startdate><enddate>202208</enddate><creator>Datta, Arindam</creator><creator>Brosh, Robert M.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202208</creationdate><title>WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer</title><author>Datta, Arindam ; Brosh, Robert M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4687-69a42a754bddeb5caba3cc55a9277e16360445d6863423849ece3df23bf8bb313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Aging</topic><topic>Aging, Premature</topic><topic>BRCA1 protein</topic><topic>BRCA2</topic><topic>BRCA2 protein</topic><topic>BRCA2 Protein - genetics</topic><topic>BRCA2 Protein - metabolism</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Chromosomal Instability</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA helicase</topic><topic>DNA Helicases - chemistry</topic><topic>DNA repair</topic><topic>DNA Replication</topic><topic>Exodeoxyribonucleases - genetics</topic><topic>Exodeoxyribonucleases - metabolism</topic><topic>Exonuclease</topic><topic>genetic disease</topic><topic>Genomic instability</topic><topic>Humans</topic><topic>Metabolism</topic><topic>Mutation</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - genetics</topic><topic>Ovarian cancer</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Replication</topic><topic>Replication forks</topic><topic>replication stress</topic><topic>synthetic lethality</topic><topic>Telomeres</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><topic>Werner Syndrome - genetics</topic><topic>Werner Syndrome - metabolism</topic><topic>Werner Syndrome Helicase - genetics</topic><topic>Werner Syndrome Helicase - metabolism</topic><topic>Werner's syndrome</topic><topic>WRN</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Datta, Arindam</creatorcontrib><creatorcontrib>Brosh, Robert M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BioEssays</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Datta, Arindam</au><au>Brosh, Robert M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer</atitle><jtitle>BioEssays</jtitle><addtitle>Bioessays</addtitle><date>2022-08</date><risdate>2022</risdate><volume>44</volume><issue>8</issue><spage>e2200057</spage><epage>n/a</epage><pages>e2200057-n/a</pages><issn>0265-9247</issn><eissn>1521-1878</eissn><abstract>Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double‐strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN‐BRCA2 genetic interaction under conditions of replication stress.
Suppression of WRN helicase's action to remodel stalled DNA replication forks in BRCA2‐deficient cancer cells causes genomic instability and cancer cell killing. Created with BioRender.com.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>35751457</pmid><doi>10.1002/bies.202200057</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aging Aging, Premature BRCA1 protein BRCA2 BRCA2 protein BRCA2 Protein - genetics BRCA2 Protein - metabolism Breast cancer Cancer Chromosomal Instability Deoxyribonucleic acid DNA DNA helicase DNA Helicases - chemistry DNA repair DNA Replication Exodeoxyribonucleases - genetics Exodeoxyribonucleases - metabolism Exonuclease genetic disease Genomic instability Humans Metabolism Mutation Neoplasms - drug therapy Neoplasms - genetics Ovarian cancer Poly(ADP-ribose) polymerase Replication Replication forks replication stress synthetic lethality Telomeres Tumor suppressor genes Tumors Werner Syndrome - genetics Werner Syndrome - metabolism Werner Syndrome Helicase - genetics Werner Syndrome Helicase - metabolism Werner's syndrome WRN |
| title | WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer |
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