Loss of SIM2s inhibits RAD51 binding and leads to unresolved replication stress.
Background: Mutations in genes associated with homologous recombination (HR) increase an individual's risk of developing triple-negative breast cancer (TNBC). Although known for their role in repairing dsDNA breaks, HR repair elements also stabilize and restart stalled replication forks. Essential t...
| Publicado en: | Breast Cancer Research Vol. 21; no. 1 |
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| Autores principales: | , , , , , |
| Formato: | Journal Article |
| Publicado: |
BioMed Central
11/27/2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=139882369&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 139882369 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 11/27/2019 vid: 21 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 139882369 139882369 NLM31775907 10.1186/s13058-019-1207-z NLM31775907 139882369 ppct: 1 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Loss of SIM2s inhibits RAD51 binding and leads to unresolved replication stress. aug: au: Pearson, Scott J. Elswood, Jessica Barhoumi, Rola Ming-Whitfield, Brittini Rijnkels, Monique Porter, Weston W. affil: Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, 77843, College Station, TX, USA sug: subj: Proteins DNA Stress, Physiological Chromosomes Metabolism Proteins Metabolism Chromosomes Animals Mutation Cell Line, Tumor Mice Epithelial Cells Metabolism ab: Background: Mutations in genes associated with homologous recombination (HR) increase an individual's risk of developing triple-negative breast cancer (TNBC). Although known for their role in repairing dsDNA breaks, HR repair elements also stabilize and restart stalled replication forks. Essential to these functions are RAD51 and its paralogs, each of which has a unique role in preventing replication fork collapse and restart. However, progress toward understanding the regulation of these factors has been slow. With such a pivotal role in the maintenance of genomic integrity, furthering our understanding of this pathway through the discovery of new factors involved in HR is important. Recently, we showed that singleminded-2s (SIM2s) is stabilized in response to dsDNA breaks and is required for effective HR.Methods: Initial analysis of the effect loss of SIM2s has on replication stress resolution was conducted using DNA combing assays in established breast cancer cell lines. Further analysis was conducted via immunostaining to determine the effect loss of SIM2s has on factor recruitment. In vivo confirmation was achieved through the use of a mammary epithelial cell conditional knockout mouse model before SIM2s' role in RAD51 recruitment was determined by immunoblotting.Results: Here, we show loss of SIM2s decreases replication fork stability, leading to fork collapse in response to genotoxic stress. Furthermore, loss of SIM2s results in aberrant separation of sister chromatids during mitosis, which has been previously shown to result in chromosomal fragmentation and aneuploidy. Interestingly, loss of SIM2s was shown to result in failure of RAD51 to localize to sites of replication stress in both breast cancer cell lines and primary mammary epithelial cells. Finally, we observed SIM2 is stabilized in response to genotoxic stress and interacts with RAD51, which is necessary for RAD51-DNA binding.Conclusions: Together, these results show a role for SIM2s in the resolution of replication stress and further characterize the necessity of SIM2s for effective RAD51 loading in response to DNA damage or stress, ultimately promoting genomic integrity and thus preventing the accumulation of cancer-promoting mutations. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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