title: Kub5-Hera, the human Rtt103 homolog, plays dual functional roles in transcription termination and DNA repair.
abstract: Functions of Kub5-Hera (In Greek Mythology Hera controlled Artemis) (K-H), the human homolog of the yeast transcription termination factor Rtt103, remain undefined. Here, we show that K-H has functions in both transcription termination and DNA double-strand break (DSB) repair. K-H forms distinct protein complexes with factors that repair DSBs (e.g. Ku70, Ku86, Artemis) and terminate transcription (e.g. RNA polymerase II). K-H loss resulted in increased basal R-loop levels, DSBs, activated DNA-damage responses and enhanced genomic instability. Significantly lowered Artemis protein levels were detected in K-H knockdown cells, which were restored with specific K-H cDNA re-expression. K-H deficient cells were hypersensitive to cytotoxic agents that induce DSBs, unable to reseal complex DSB ends, and showed significantly delayed γ-H2AX and 53BP1 repair-related foci regression. Artemis re-expression in K-H-deficient cells restored DNA-repair function and resistance to DSB-inducing agents. However, R loops persisted consistent with dual roles of K-H in transcription termination and DSB repair.
authors.affiliation: Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8807, USA, Department of Biological Sciences, Columbia University, New York, NY 10027, USA, Laboratory of Genetics, Salk Institute of Biological Studies, La Jolla, CA 92037, USA, Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH 44106, USA and Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morales
authors.forename: Patricia
authors.initials: P
authors.lastname: Richard
authors.forename: Amy
authors.initials: A
authors.lastname: Rommel
authors.forename: Farjana J
authors.initials: FJ
authors.lastname: Fattah
authors.forename: Edward A
authors.initials: EA
authors.lastname: Motea
authors.forename: Praveen L
authors.initials: PL
authors.lastname: Patidar
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Konstantin
authors.initials: K
authors.lastname: Leskov
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.forename: James L
authors.initials: JL
authors.lastname: Manley
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004720:Endonucleases; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D061806:Transcription Termination, Genetic
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C571225:RPRD1B protein, human; C553428:Rtt103 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C426344:DCLRE1C protein, human; D004720:Endonucleases