Characterisation of unessential genes required for survival under conditions of DNA stress
Abstract Background Genomic instability is a hallmark of cancer. Cancer progression depends on the development and amplification of mutations that alter the cellular response to threats to the genome. This can lead to DNA replication stress and the potential loss of genetic integrity of the newly fo...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Journal of Genetic Engineering and Biotechnology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s43141-020-00025-x |
| _version_ | 1827280122029277184 |
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| author | Hassan Ahmed Ezzat Clive Price |
| author_facet | Hassan Ahmed Ezzat Clive Price |
| author_sort | Hassan Ahmed Ezzat |
| collection | DOAJ |
| description | Abstract Background Genomic instability is a hallmark of cancer. Cancer progression depends on the development and amplification of mutations that alter the cellular response to threats to the genome. This can lead to DNA replication stress and the potential loss of genetic integrity of the newly formed cells. This study utilised fission yeast to map the interactions occurring in some of the most crucial pathways in both DNA replication and checkpoint monitoring involving Rad4, the Schizosaccharomyces pombe (S. pombe) TopBP1 homologue. We have modelled conditions of replication stress in the genetically tractable fission yeast, S. pombe using the hypomorphic rad4-116 allele. Synthetic genetic analysis was used to identify processes required for cell survival under conditions of DNA replication stress. With the aim of mapping the genetic interactions of rad4 and its mutant allele, rad4-116, several genes that could have an interaction with rad4 during replication stress have emerged as attractive. Results Interactions with genes involved in chromatin remodelling, such as hip1, and replication fork stalling resolution, such as mrc1, swi1 and swi3 were explored and confirmed. The interactions of Rad4 with each of the genes provided separate and distinct tumour formation pathways, as evident in the synthetically lethal interactions. Even within the same complex, rad4-116 double mutants behaved differently proving that Rad4 interacts at different levels and functions with the same proteins. Conclusion Results from this study provide a novel view of the rad4 interactions, the association of Rad4 with the replisome. The study also provides the groundwork on a theoretical and practical level for the exploration and separation of interactions of TopBP1 with the histone chaperone family and the replisome. |
| first_indexed | 2024-04-24T08:31:30Z |
| format | Article |
| id | doaj.art-9ebc26f2ddd840cf9997516b3f9415bf |
| institution | Directory Open Access Journal |
| issn | 2090-5920 |
| language | English |
| last_indexed | 2024-04-24T08:31:30Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Genetic Engineering and Biotechnology |
| spelling | doaj.art-9ebc26f2ddd840cf9997516b3f9415bf2024-04-16T19:29:23ZengElsevierJournal of Genetic Engineering and Biotechnology2090-59202020-05-0118111710.1186/s43141-020-00025-xCharacterisation of unessential genes required for survival under conditions of DNA stressHassan Ahmed Ezzat0Clive Price1Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster UniversityDivision of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster UniversityAbstract Background Genomic instability is a hallmark of cancer. Cancer progression depends on the development and amplification of mutations that alter the cellular response to threats to the genome. This can lead to DNA replication stress and the potential loss of genetic integrity of the newly formed cells. This study utilised fission yeast to map the interactions occurring in some of the most crucial pathways in both DNA replication and checkpoint monitoring involving Rad4, the Schizosaccharomyces pombe (S. pombe) TopBP1 homologue. We have modelled conditions of replication stress in the genetically tractable fission yeast, S. pombe using the hypomorphic rad4-116 allele. Synthetic genetic analysis was used to identify processes required for cell survival under conditions of DNA replication stress. With the aim of mapping the genetic interactions of rad4 and its mutant allele, rad4-116, several genes that could have an interaction with rad4 during replication stress have emerged as attractive. Results Interactions with genes involved in chromatin remodelling, such as hip1, and replication fork stalling resolution, such as mrc1, swi1 and swi3 were explored and confirmed. The interactions of Rad4 with each of the genes provided separate and distinct tumour formation pathways, as evident in the synthetically lethal interactions. Even within the same complex, rad4-116 double mutants behaved differently proving that Rad4 interacts at different levels and functions with the same proteins. Conclusion Results from this study provide a novel view of the rad4 interactions, the association of Rad4 with the replisome. The study also provides the groundwork on a theoretical and practical level for the exploration and separation of interactions of TopBP1 with the histone chaperone family and the replisome.http://link.springer.com/article/10.1186/s43141-020-00025-xSchizosaccharomyces pombeTopBP1Eukaryotic DNA replicationDNA Fork Stalling |
| spellingShingle | Hassan Ahmed Ezzat Clive Price Characterisation of unessential genes required for survival under conditions of DNA stress Journal of Genetic Engineering and Biotechnology Schizosaccharomyces pombe TopBP1 Eukaryotic DNA replication DNA Fork Stalling |
| title | Characterisation of unessential genes required for survival under conditions of DNA stress |
| title_full | Characterisation of unessential genes required for survival under conditions of DNA stress |
| title_fullStr | Characterisation of unessential genes required for survival under conditions of DNA stress |
| title_full_unstemmed | Characterisation of unessential genes required for survival under conditions of DNA stress |
| title_short | Characterisation of unessential genes required for survival under conditions of DNA stress |
| title_sort | characterisation of unessential genes required for survival under conditions of dna stress |
| topic | Schizosaccharomyces pombe TopBP1 Eukaryotic DNA replication DNA Fork Stalling |
| url | http://link.springer.com/article/10.1186/s43141-020-00025-x |
| work_keys_str_mv | AT hassanahmedezzat characterisationofunessentialgenesrequiredforsurvivalunderconditionsofdnastress AT cliveprice characterisationofunessentialgenesrequiredforsurvivalunderconditionsofdnastress |