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

doi:10.1093/nar/gkae834

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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, Paras Gaur, Divya S Bhat, Sabryn M Labenz, Jenna E Heinen, Blaine A Williams, …

Nucleic acids research, Vol.52(20), pp.12422-12437

11/11/2024

DOI: 10.1093/nar/gkae834

PMCID: PMC11551749

PMID: 39329264

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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.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.

Details

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
Paras Gaur - University of Iowa
Divya S Bhat - University of Iowa
Sabryn M Labenz - University of Northern Iowa
Jenna E Heinen - University of Northern Iowa
Blaine A Williams - University of Northern Iowa
S M Ali Tabei - University of Northern Iowa
Marcin W Wlodarski - St. Jude Children's Research Hospital
Edwin Antony - Saint Louis University
Maria Spies - University of Iowa
Resource Type: Journal article
Publication Details: Nucleic acids research, Vol.52(20), pp.12422-12437
DOI: 10.1093/nar/gkae834
PMID: 39329264
PMCID: PMC11551749
NLM abbreviation: Nucleic Acids Res
ISSN: 1362-4962
eISSN: 1362-4962
Publisher: OXFORD UNIV PRESS
Grant note: National Institutes of Health: R35GM131704, GM133967, GM130756, GM149320, OD030343 American Society of Hematology Research Training Awards for Fellows: K08 DK134873 NIH NCI T32 in Free Radicals and Radiation Biology training program: CA078586
National Institutes of Health [R35GM131704 to M.S., GM133967, GM130756, GM149320 and OD030343 to E.A.]; R.S. was supported by American Society of Hematology Research Training Awards for Fellows [K08 DK134873]; M.R. was supported by a postdoctoral fellowship from the NIH NCI T32 in Free Radicals and Radiation Biology training program [CA078586]. The open access publication charge for this paper has been waived by Oxford University Press - NAR Editorial Board members are entitled to one free paper per year in recognition of their work on behalf of the journal.
Language: English
Electronic publication date: 09/26/2024
Date published: 11/11/2024
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984721131302771

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