title: Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair.
abstract: DNA double-strand break (DSB) signaling and repair are critical for cell viability, and rely on highly coordinated pathways whose molecular organization is still incompletely understood. Here, we show that heterogeneous nuclear ribonucleoprotein U-like (hnRNPUL) proteins 1 and 2 play key roles in cellular responses to DSBs. We identify human hnRNPUL1 and -2 as binding partners for the DSB sensor complex MRE11-RAD50-NBS1 (MRN) and demonstrate that hnRNPUL1 and -2 are recruited to DNA damage in an interdependent manner that requires MRN. Moreover, we show that hnRNPUL1 and -2 stimulate DNA-end resection and promote ATR-dependent signaling and DSB repair by homologous recombination, thereby contributing to cell survival upon exposure to DSB-inducing agents. Finally, we establish that hnRNPUL1 and -2 function downstream of MRN and CtBP-interacting protein (CtIP) to promote recruitment of the BLM helicase to DNA breaks. Collectively, these results provide insights into how mammalian cells respond to DSBs.
authors.affiliation: The Gurdon Institute, Department of Biochemistry, University of Cambridge, UK.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Polo
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Blackford
authors.forename: J Ross
authors.initials: JR
authors.lastname: Chapman
authors.forename: Linda
authors.initials: L
authors.lastname: Baskcomb
authors.forename: Serge
authors.initials: S
authors.lastname: Gravel
authors.forename: Andre
authors.initials: A
authors.lastname: Rusch
authors.forename: Anoushka
authors.initials: A
authors.lastname: Thomas
authors.forename: Rachel
authors.initials: R
authors.lastname: Blundred
authors.forename: Philippa
authors.initials: P
authors.lastname: Smith
authors.forename: Julia
authors.initials: J
authors.lastname: Kzhyshkowska
authors.forename: Thomas
authors.initials: T
authors.lastname: Dobner
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Turnell
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Grand
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D017766:Acid Anhydride Hydrolases; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C475078:HNRNPUL1 protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C571738:hnRNPUL2 protein, human; D004706:Endodeoxyribonucleases; D000076228:MRE11 Homologue Protein; C410741:RBBP8 protein, human; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes