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CRISPR-Cas13d screens identify KILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair.

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Názov: CRISPR-Cas13d screens identify KILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair.
Autori: Wang, Lu, Bitar, Mainá, Lu, Xue, Jacquelin, Sebastien, Nair, Sneha, Sivakumaran, Haran, Hillman, Kristine M., Kaufmann, Susanne, Ziegman, Rebekah, Casciello, Francesco, Gowda, Harsha, Rosenbluh, Joseph, Edwards, Stacey L., French, Juliet D.
Zdroj: Molecular Cancer; 5/15/2024, Vol. 23 Issue 1, p1-17, 17p
Predmety: DNA replication, BREAST cancer, DNA repair, CANCER cell proliferation, LINCRNA, SYNCRIP protein
Abstrakt: Background: Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered 844 lncRNAs that were genetically linked to breast cancer through genome-wide association studies (GWAS). Here, we show that a subset of these lncRNAs alter breast cancer risk by modulating cell proliferation, and provide evidence that a reduced expression on one lncRNA increases breast cancer risk through aberrant DNA replication and repair. Methods: We performed pooled CRISPR-Cas13d-based knockdown screens in breast cells to identify which of the 844 breast cancer-associated lncRNAs alter cell proliferation. We selected one of the lncRNAs that increased cell proliferation, KILR, for follow-up functional studies. KILR pull-down followed by mass spectrometry was used to identify binding proteins. Knockdown and overexpression studies were performed to assess the mechanism by which KILR regulates proliferation. Results: We show that KILR functions as a tumor suppressor, safeguarding breast cells against uncontrolled proliferation. The half-life of KILR is significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. Mechanistically, KILR sequesters RPA1, a subunit of the RPA complex required for DNA replication and repair. Reduced KILR expression promotes breast cancer cell proliferation by increasing the available pool of RPA1 and speed of DNA replication. Conversely, KILR overexpression promotes apoptosis in breast cancer cells, but not normal breast cells. Conclusions: Our results confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Cancer is the property of BioMed Central and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Label: Title
  Group: Ti
  Data: CRISPR-Cas13d screens identify KILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair.
– Name: Author
  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Wang%2C+Lu%22">Wang, Lu</searchLink><br /><searchLink fieldCode="AR" term="%22Bitar%2C+Mainá%22">Bitar, Mainá</searchLink><br /><searchLink fieldCode="AR" term="%22Lu%2C+Xue%22">Lu, Xue</searchLink><br /><searchLink fieldCode="AR" term="%22Jacquelin%2C+Sebastien%22">Jacquelin, Sebastien</searchLink><br /><searchLink fieldCode="AR" term="%22Nair%2C+Sneha%22">Nair, Sneha</searchLink><br /><searchLink fieldCode="AR" term="%22Sivakumaran%2C+Haran%22">Sivakumaran, Haran</searchLink><br /><searchLink fieldCode="AR" term="%22Hillman%2C+Kristine+M%2E%22">Hillman, Kristine M.</searchLink><br /><searchLink fieldCode="AR" term="%22Kaufmann%2C+Susanne%22">Kaufmann, Susanne</searchLink><br /><searchLink fieldCode="AR" term="%22Ziegman%2C+Rebekah%22">Ziegman, Rebekah</searchLink><br /><searchLink fieldCode="AR" term="%22Casciello%2C+Francesco%22">Casciello, Francesco</searchLink><br /><searchLink fieldCode="AR" term="%22Gowda%2C+Harsha%22">Gowda, Harsha</searchLink><br /><searchLink fieldCode="AR" term="%22Rosenbluh%2C+Joseph%22">Rosenbluh, Joseph</searchLink><br /><searchLink fieldCode="AR" term="%22Edwards%2C+Stacey+L%2E%22">Edwards, Stacey L.</searchLink><br /><searchLink fieldCode="AR" term="%22French%2C+Juliet+D%2E%22">French, Juliet D.</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: Molecular Cancer; 5/15/2024, Vol. 23 Issue 1, p1-17, 17p
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22DNA+replication%22">DNA replication</searchLink><br /><searchLink fieldCode="DE" term="%22BREAST+cancer%22">BREAST cancer</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+repair%22">DNA repair</searchLink><br /><searchLink fieldCode="DE" term="%22CANCER+cell+proliferation%22">CANCER cell proliferation</searchLink><br /><searchLink fieldCode="DE" term="%22LINCRNA%22">LINCRNA</searchLink><br /><searchLink fieldCode="DE" term="%22SYNCRIP+protein%22">SYNCRIP protein</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered 844 lncRNAs that were genetically linked to breast cancer through genome-wide association studies (GWAS). Here, we show that a subset of these lncRNAs alter breast cancer risk by modulating cell proliferation, and provide evidence that a reduced expression on one lncRNA increases breast cancer risk through aberrant DNA replication and repair. Methods: We performed pooled CRISPR-Cas13d-based knockdown screens in breast cells to identify which of the 844 breast cancer-associated lncRNAs alter cell proliferation. We selected one of the lncRNAs that increased cell proliferation, KILR, for follow-up functional studies. KILR pull-down followed by mass spectrometry was used to identify binding proteins. Knockdown and overexpression studies were performed to assess the mechanism by which KILR regulates proliferation. Results: We show that KILR functions as a tumor suppressor, safeguarding breast cells against uncontrolled proliferation. The half-life of KILR is significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. Mechanistically, KILR sequesters RPA1, a subunit of the RPA complex required for DNA replication and repair. Reduced KILR expression promotes breast cancer cell proliferation by increasing the available pool of RPA1 and speed of DNA replication. Conversely, KILR overexpression promotes apoptosis in breast cancer cells, but not normal breast cells. Conclusions: Our results confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Molecular Cancer is the property of BioMed Central and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1186/s12943-024-02021-y
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      – Code: eng
        Text: English
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      – SubjectFull: DNA repair
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      – SubjectFull: CANCER cell proliferation
        Type: general
      – SubjectFull: LINCRNA
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      – SubjectFull: SYNCRIP protein
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      – TitleFull: CRISPR-Cas13d screens identify KILR, a breast cancer risk-associated lncRNA that regulates DNA replication and repair.
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              M: 05
              Text: 5/15/2024
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