Human hnRNPA1 reorganizes telomere-bound Replication Protein A

Sophie L Granger; Richa Sharma; Vikas Kaushik; Mortezaali Razzaghi; Masayoshi Honda; Divya S Bhat; Marcin Wlodarski; Edwin Antony; Maria Spies

doi:10.1101/2023.05.09.540056

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Human hnRNPA1 reorganizes telomere-bound Replication Protein A

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Human hnRNPA1 reorganizes telomere-bound Replication Protein A

Sophie L Granger, Richa Sharma, Vikas Kaushik, Mortezaali Razzaghi, Masayoshi Honda, Divya S Bhat, Marcin Wlodarski, Edwin Antony and Maria Spies

bioRxiv : the preprint server for biology

05/12/2023

DOI: 10.1101/2023.05.09.540056

PMCID: PMC10197631

PMID: 37214874

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https://doi.org/10.1101/2023.05.09.540056View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Human replication protein A (RPA) is a heterotrimeric ssDNA binding protein responsible for many aspects of cellular DNA metabolism. The binding to and dissociation of the four individual DNA binding domains (DBDs) from DNA result in configurational dynamics of the RPA-DNA complexes which are essential for replacement of RPA by downstream proteins in various cellular metabolic pathways. RPA plays several important functions at telomeres where it binds to and melts telomeric G-quadruplexes, non-canonical DNA structures formed at the G-rich telomeric ssDNA overhangs. Here, we combine single-molecule total internal reflection fluorescence microscopy (smTIRFM), mass photometry (MP) with biophysical and biochemical analyses, of a gain-of-function RPA mutant to demonstrate that heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) specifically remodels RPA bound to telomeric ssDNA by dampening the RPA configurational dynamics and forming a stable ternary complex. Uniquely among hnRNPA1 target RNAs, TERRA is capable of releasing hnRNPA1 from the RPA-telomeric DNA complex. We speculate that this telomere specific RPA-DNA-hnRNPA1 complex is an important structure in telomere protection. One Sentence SummaryAt the single-stranded ends of human telomeres, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) binds to and modulates conformational dynamics of the ssDNA binding protein RPA forming a ternary complex which is controlled by TERRA RNA.

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Title: Subtitle: Human hnRNPA1 reorganizes telomere-bound Replication Protein A
Creators: Sophie L Granger - University of Iowa
Richa Sharma - St. Jude Children's Research Hospital
Vikas Kaushik - Saint Louis University
Mortezaali Razzaghi - University of Iowa
Masayoshi Honda - University of Iowa
Divya S Bhat - University of Iowa
Marcin Wlodarski - St. Jude Children's Research Hospital
Edwin Antony - Saint Louis University
Maria Spies - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.05.09.540056
PMID: 37214874
PMCID: PMC10197631
Language: English
Date posted: 05/12/2023
Academic Unit: Biochemistry and Molecular Biology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology
Record Identifier: 9984419453802771

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