{"doi":"10.1242/jcs.244129","title":"TDP-43 dysfunction results in R-loop accumulation and DNA replication defects","abstract":"TAR DNA-binding protein 43 (TDP-43; also known as TARDBP) is an RNA-binding protein whose aggregation is a hallmark of the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 loss increases DNA damage and compromises cell viability, but the actual function of TDP-43 in preventing genome instability remains unclear. Here, we show that loss of TDP-43 increases R-loop formation in a transcription-dependent manner and results in DNA replication stress. TDP-43 nucleic-acid-binding and self-assembly activities are important in inhibiting R-loop accumulation and preserving normal DNA replication. We also found that TDP-43 cytoplasmic aggregation impairs TDP-43 function in R-loop regulation. Furthermore, increased R-loop accumulation and DNA damage is observed in neurons upon loss of TDP-43. Together, our findings indicate that TDP-43 function and normal protein homeostasis are crucial in maintaining genomic stability through a co-transcriptional process that prevents aberrant R-loop accumulation. We propose that the increased R-loop formation and genomic instability associated with TDP-43 loss are linked to the pathogenesis of TDP-43 proteinopathies.This article has an associated First Person interview with the first author of the paper.","journal":"Journal of Cell Science","year":2020,"id":57668,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":77,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9649,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":301611,"name":"Annabel Quinet","orcid":"0000-0003-0852-6181","position":1,"is_corresponding":false},{"id":301612,"name":"Yea‐Lih Lin","orcid":"0000-0003-4063-0771","position":2,"is_corresponding":false},{"id":250202,"name":"Albert A. Davis","orcid":"0000-0003-2042-8445","position":3,"is_corresponding":false},{"id":247519,"name":"Philippe Pasero","orcid":"0000-0001-5891-0822","position":4,"is_corresponding":false},{"id":301613,"name":"Yuna M. Ayala","orcid":"0000-0003-4688-6583","position":5,"is_corresponding":false},{"id":301614,"name":"Alessandro Vindigni","orcid":"0000-0002-0568-5067","position":6,"is_corresponding":false},{"id":301610,"name":"Matthew Wood","orcid":"0000-0003-2288-1112","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-18T21:06:48.611399Z","pmid":"32989039","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}