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Human RPA is an essential telomerase processivity factor for maintaining telomeres.

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Title: Human RPA is an essential telomerase processivity factor for maintaining telomeres.
Authors: Agrawal, Sourav (AUTHOR), Lin, Xiuhua (AUTHOR), Susvirkar, Vivek (AUTHOR), O'Connor, Michael S. (AUTHOR), Chavez, Bianca L. (AUTHOR), Tholkes, Victoria R. (AUTHOR), Tauber, Grace P. (AUTHOR), He, Qixiang (AUTHOR), Abe, Kaitlyn M. (AUTHOR), Huang, Xuhui (AUTHOR), Lim, Ci Ji (AUTHOR)
Source: Science. 10/30/2025, Vol. 390 Issue 6772, p495-502. 8p.
Subjects: Telomerase, Replication protein A, Telomeres, DNA replication, Genetic mutation, DNA-ligand interactions, Telomerization, Telomerase reverse transcriptase
Abstract: Telomerase counteracts telomere shortening by repeatedly adding DNA repeats to chromosome ends. We identified the replication protein A (RPA) heterotrimer as a telomerase processivity factor critical for telomere maintenance. RPA stimulates telomerase processivity in vitro, and AlphaFold modeling predicts that RPA engages a telomerase surface distinct from the one bound by the shelterin subunit TPP1. Guided by these predictions, we engineered separation-of-function telomerase reverse transcriptase (TERT) mutants and found that the loss of RPA-mediated stimulation impairs telomere elongation, even when TPP1–POT1–mediated stimulation remains intact. Furthermore, short-telomere disease–associated TERT mutations reduce RPA-dependent telomerase stimulation, revealing a mechanistic link between impaired processivity and telomeropathies. Together, our findings establish human RPA as a key regulator of telomerase and offer molecular insights into telomere-related disease mechanisms. Editor's summary: Human replication protein A (RPA), long recognized as an essential factor in DNA replication and repair, has now been found to play a critical role at chromosome ends. Agrawal et al. demonstrated that RPA directly enhances the processivity of telomerase, the enzyme responsible for extending telomeres. By boosting telomerase's ability to add repeated DNA sequences, RPA proves vital for maintaining telomere length and genomic stability. This repurposing of a fundamental single-stranded DNA-binding complex provides fresh insights into telomere regulation and has implications for aging, cancer, and telomere-related disorders. —Di Jiang [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science 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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  Data: Human RPA is an essential telomerase processivity factor for maintaining telomeres.
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  Data: <searchLink fieldCode="AR" term="%22Agrawal%2C+Sourav%22">Agrawal, Sourav</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lin%2C+Xiuhua%22">Lin, Xiuhua</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Susvirkar%2C+Vivek%22">Susvirkar, Vivek</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22O'Connor%2C+Michael+S%2E%22">O'Connor, Michael S.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chavez%2C+Bianca+L%2E%22">Chavez, Bianca L.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Tholkes%2C+Victoria+R%2E%22">Tholkes, Victoria R.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Tauber%2C+Grace+P%2E%22">Tauber, Grace P.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22He%2C+Qixiang%22">He, Qixiang</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Abe%2C+Kaitlyn+M%2E%22">Abe, Kaitlyn M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Huang%2C+Xuhui%22">Huang, Xuhui</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lim%2C+Ci+Ji%22">Lim, Ci Ji</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 10/30/2025, Vol. 390 Issue 6772, p495-502. 8p.
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  Data: <searchLink fieldCode="DE" term="%22Telomerase%22">Telomerase</searchLink><br /><searchLink fieldCode="DE" term="%22Replication+protein+A%22">Replication protein A</searchLink><br /><searchLink fieldCode="DE" term="%22Telomeres%22">Telomeres</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+replication%22">DNA replication</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+mutation%22">Genetic mutation</searchLink><br /><searchLink fieldCode="DE" term="%22DNA-ligand+interactions%22">DNA-ligand interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Telomerization%22">Telomerization</searchLink><br /><searchLink fieldCode="DE" term="%22Telomerase+reverse+transcriptase%22">Telomerase reverse transcriptase</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Telomerase counteracts telomere shortening by repeatedly adding DNA repeats to chromosome ends. We identified the replication protein A (RPA) heterotrimer as a telomerase processivity factor critical for telomere maintenance. RPA stimulates telomerase processivity in vitro, and AlphaFold modeling predicts that RPA engages a telomerase surface distinct from the one bound by the shelterin subunit TPP1. Guided by these predictions, we engineered separation-of-function telomerase reverse transcriptase (TERT) mutants and found that the loss of RPA-mediated stimulation impairs telomere elongation, even when TPP1–POT1–mediated stimulation remains intact. Furthermore, short-telomere disease–associated TERT mutations reduce RPA-dependent telomerase stimulation, revealing a mechanistic link between impaired processivity and telomeropathies. Together, our findings establish human RPA as a key regulator of telomerase and offer molecular insights into telomere-related disease mechanisms. Editor's summary: Human replication protein A (RPA), long recognized as an essential factor in DNA replication and repair, has now been found to play a critical role at chromosome ends. Agrawal et al. demonstrated that RPA directly enhances the processivity of telomerase, the enzyme responsible for extending telomeres. By boosting telomerase's ability to add repeated DNA sequences, RPA proves vital for maintaining telomere length and genomic stability. This repurposing of a fundamental single-stranded DNA-binding complex provides fresh insights into telomere regulation and has implications for aging, cancer, and telomere-related disorders. —Di Jiang [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science 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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      – Type: doi
        Value: 10.1126/science.ads5297
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      – Code: eng
        Text: English
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        PageCount: 8
        StartPage: 495
    Subjects:
      – SubjectFull: Telomerase
        Type: general
      – SubjectFull: Replication protein A
        Type: general
      – SubjectFull: Telomeres
        Type: general
      – SubjectFull: DNA replication
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      – SubjectFull: Genetic mutation
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      – SubjectFull: DNA-ligand interactions
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      – SubjectFull: Telomerization
        Type: general
      – SubjectFull: Telomerase reverse transcriptase
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      – TitleFull: Human RPA is an essential telomerase processivity factor for maintaining telomeres.
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              Text: 10/30/2025
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