DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex
Repair of a DNA double-strand break relies upon a pathway of proteins to identify damage, regulate cell cycle checkpoints, and repair the damage. This process is initiated by a sensor protein complex, the MRN complex, comprised of three proteins-MRE11, RAD50, and NBS1. After a double-stranded break,...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/21/5278 |
| _version_ | 1797468839759314944 |
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| author | Claire McCarthy-Leo Fatima Darwiche Michael A. Tainsky |
| author_facet | Claire McCarthy-Leo Fatima Darwiche Michael A. Tainsky |
| author_sort | Claire McCarthy-Leo |
| collection | DOAJ |
| description | Repair of a DNA double-strand break relies upon a pathway of proteins to identify damage, regulate cell cycle checkpoints, and repair the damage. This process is initiated by a sensor protein complex, the MRN complex, comprised of three proteins-MRE11, RAD50, and NBS1. After a double-stranded break, the MRN complex recruits and activates ATM, in-turn activating other proteins such as BRCA1/2, ATR, CHEK1/2, PALB2 and RAD51. These proteins have been the focus of many studies for their individual roles in hereditary cancer syndromes and are included on several genetic testing panels. These panels have enabled us to acquire large amounts of genetic data, much of which remains a challenge to interpret due to the presence of variants of uncertain significance (VUS). While the primary aim of clinical testing is to accurately and confidently classify variants in order to inform medical management, the presence of VUSs has led to ambiguity in genetic counseling. Pathogenic variants within MRN complex genes have been implicated in breast, ovarian, prostate, colon cancers and gliomas; however, the hundreds of VUSs within <i>MRE11, RAD50,</i> and <i>NBS1</i> precludes the application of these data in genetic guidance of carriers. In this review, we discuss the MRN complex’s role in DNA double-strand break repair, its interactions with other cancer predisposing genes, the variants that can be found within the three MRN complex genes, and the MRN complex’s potential as an anti-cancer therapeutic target. |
| first_indexed | 2024-03-09T19:13:00Z |
| format | Article |
| id | doaj.art-22a26eac350044e08eeddd01de2c0895 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T19:13:00Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-22a26eac350044e08eeddd01de2c08952023-11-24T04:01:57ZengMDPI AGCancers2072-66942022-10-011421527810.3390/cancers14215278DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN ComplexClaire McCarthy-Leo0Fatima Darwiche1Michael A. Tainsky2Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USACenter for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USACenter for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USARepair of a DNA double-strand break relies upon a pathway of proteins to identify damage, regulate cell cycle checkpoints, and repair the damage. This process is initiated by a sensor protein complex, the MRN complex, comprised of three proteins-MRE11, RAD50, and NBS1. After a double-stranded break, the MRN complex recruits and activates ATM, in-turn activating other proteins such as BRCA1/2, ATR, CHEK1/2, PALB2 and RAD51. These proteins have been the focus of many studies for their individual roles in hereditary cancer syndromes and are included on several genetic testing panels. These panels have enabled us to acquire large amounts of genetic data, much of which remains a challenge to interpret due to the presence of variants of uncertain significance (VUS). While the primary aim of clinical testing is to accurately and confidently classify variants in order to inform medical management, the presence of VUSs has led to ambiguity in genetic counseling. Pathogenic variants within MRN complex genes have been implicated in breast, ovarian, prostate, colon cancers and gliomas; however, the hundreds of VUSs within <i>MRE11, RAD50,</i> and <i>NBS1</i> precludes the application of these data in genetic guidance of carriers. In this review, we discuss the MRN complex’s role in DNA double-strand break repair, its interactions with other cancer predisposing genes, the variants that can be found within the three MRN complex genes, and the MRN complex’s potential as an anti-cancer therapeutic target.https://www.mdpi.com/2072-6694/14/21/5278MRN complexDNA repair pathwayvariants of uncertain significance |
| spellingShingle | Claire McCarthy-Leo Fatima Darwiche Michael A. Tainsky DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex Cancers MRN complex DNA repair pathway variants of uncertain significance |
| title | DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex |
| title_full | DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex |
| title_fullStr | DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex |
| title_full_unstemmed | DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex |
| title_short | DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex |
| title_sort | dna repair mechanisms protein interactions and therapeutic targeting of the mrn complex |
| topic | MRN complex DNA repair pathway variants of uncertain significance |
| url | https://www.mdpi.com/2072-6694/14/21/5278 |
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