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[Preprint]. 2024 Apr 3:2023.05.09.540056.
doi: 10.1101/2023.05.09.540056.

Human hnRNPA1 reorganizes telomere-bound Replication Protein A

Sophie L Granger, Richa Sharma, Vikas Kaushik, Mortezaali Razzaghi, Masayoshi Honda, Paras Gaur, Divya S Bhat, Sabryn M Labenz, Jenna E Heinen, Blaine A Williams, S M Ali Tabei, Marcin W Wlodarski, Edwin Antony, Maria Spies

Human hnRNPA1 reorganizes telomere-bound Replication Protein A

Sophie L Granger et al. bioRxiv. .

Update in

  • Human hnRNPA1 reorganizes telomere-bound replication protein A.
    Granger SL, Sharma R, Kaushik V, Razzaghi M, Honda M, Gaur P, Bhat DS, Labenz SM, Heinen JE, Williams BA, Tabei SMA, Wlodarski MW, Antony E, Spies M. Granger SL, et al. Nucleic Acids Res. 2024 Nov 11;52(20):12422-12437. doi: 10.1093/nar/gkae834. Nucleic Acids Res. 2024. PMID: 39329264 Free PMC article.

Abstract

Human replication protein A (RPA) is a heterotrimeric ssDNA binding protein responsible for many aspects of cellular DNA metabolism. Dynamic interactions of the four RPA DNA binding domains (DBDs) with DNA control 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) and mass photometry (MP) with biophysical and biochemical analyses to demonstrate that heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) specifically remodels RPA bound to telomeric ssDNA by dampening the RPA configurational dynamics and forming a ternary complex. Uniquely, among hnRNPA1 target RNAs, telomeric repeat-containing RNA (TERRA) is selectively 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 summary: At 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 telomeric repeat-containing RNA (TERRA).

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