F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers
Homologous recombination (HR) is the major mechanism of rescue of stalled replication forks or repair of DNA double-strand breaks (DSBs) during S phase or mitosis. In human cells, HR is facilitated by the BRCA2-BRCA1-PALB2 module, which loads the RAD51 recombinase onto a resected single-stranded DNA...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/18/4439 |
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| author | Alizhah J. Watson Michaela L. Shaffer Renee A. Bouley Ruben C. Petreaca |
| author_facet | Alizhah J. Watson Michaela L. Shaffer Renee A. Bouley Ruben C. Petreaca |
| author_sort | Alizhah J. Watson |
| collection | DOAJ |
| description | Homologous recombination (HR) is the major mechanism of rescue of stalled replication forks or repair of DNA double-strand breaks (DSBs) during S phase or mitosis. In human cells, HR is facilitated by the BRCA2-BRCA1-PALB2 module, which loads the RAD51 recombinase onto a resected single-stranded DNA end to initiate repair. Although the process is essential for error-free repair, unrestrained HR can cause chromosomal rearrangements and genome instability. F-box DNA Helicase 1 (FBH1) antagonizes the role of BRCA2-BRCA1-PALB2 to restrict hyper-recombination and prevent genome instability. Here, we analyzed reported FBH1 mutations in cancer cells using the Catalogue of Somatic Mutations in Cancers (COSMIC) to understand how they interact with the BRCA2-BRCA1-PALB2. Consistent with previous results from yeast, we find that FBH1 mutations co-occur with BRCA2 mutations and to some degree BRCA1 and PALB2. We also describe some co-occurring mutations with RAD52, the accessory RAD51 loader and facilitator of single-strand annealing, which is independent of RAD51. In silico modeling was used to investigate the role of key FBH1 mutations on protein function, and a Q650K mutation was found to destabilize the protein structure. Taken together, this work highlights how mutations in several DNA damage repair genes contribute to cellular transformation and immortalization. |
| first_indexed | 2024-03-10T22:57:03Z |
| format | Article |
| id | doaj.art-3ac08fe0fa844238b8cd41d84a37e1f3 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T22:57:03Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3ac08fe0fa844238b8cd41d84a37e1f32023-11-19T09:53:50ZengMDPI AGCancers2072-66942023-09-011518443910.3390/cancers15184439F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human CancersAlizhah J. Watson0Michaela L. Shaffer1Renee A. Bouley2Ruben C. Petreaca3Biology Program, The Ohio State University, Marion, OH 433023, USABiology Program, The Ohio State University, Marion, OH 433023, USADepartment of Chemistry and Biochemistry, The Ohio State University, Marion, OH 43302, USADepartment of Molecular Genetics, The Ohio State University, Marion, OH 43302, USAHomologous recombination (HR) is the major mechanism of rescue of stalled replication forks or repair of DNA double-strand breaks (DSBs) during S phase or mitosis. In human cells, HR is facilitated by the BRCA2-BRCA1-PALB2 module, which loads the RAD51 recombinase onto a resected single-stranded DNA end to initiate repair. Although the process is essential for error-free repair, unrestrained HR can cause chromosomal rearrangements and genome instability. F-box DNA Helicase 1 (FBH1) antagonizes the role of BRCA2-BRCA1-PALB2 to restrict hyper-recombination and prevent genome instability. Here, we analyzed reported FBH1 mutations in cancer cells using the Catalogue of Somatic Mutations in Cancers (COSMIC) to understand how they interact with the BRCA2-BRCA1-PALB2. Consistent with previous results from yeast, we find that FBH1 mutations co-occur with BRCA2 mutations and to some degree BRCA1 and PALB2. We also describe some co-occurring mutations with RAD52, the accessory RAD51 loader and facilitator of single-strand annealing, which is independent of RAD51. In silico modeling was used to investigate the role of key FBH1 mutations on protein function, and a Q650K mutation was found to destabilize the protein structure. Taken together, this work highlights how mutations in several DNA damage repair genes contribute to cellular transformation and immortalization.https://www.mdpi.com/2072-6694/15/18/4439DNA damagegenetic recombinationhelicasecancer |
| spellingShingle | Alizhah J. Watson Michaela L. Shaffer Renee A. Bouley Ruben C. Petreaca F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers Cancers DNA damage genetic recombination helicase cancer |
| title | F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers |
| title_full | F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers |
| title_fullStr | F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers |
| title_full_unstemmed | F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers |
| title_short | F-box DNA Helicase 1 (FBH1) Contributes to the Destabilization of DNA Damage Repair Machinery in Human Cancers |
| title_sort | f box dna helicase 1 fbh1 contributes to the destabilization of dna damage repair machinery in human cancers |
| topic | DNA damage genetic recombination helicase cancer |
| url | https://www.mdpi.com/2072-6694/15/18/4439 |
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