Kub5-Hera, the human Rtt103 homolog, plays dual functional roles in transcription termination and DNA repair

Julio C. Morales, Patricia Richard, Amy Rommel, Farjana J. Fattah, Edward A. Motea, Praveen L. Patidar, Ling Xiao, Konstantin Leskov, Shwu Yuan Wu, Walter N. Hittelman, Cheng Ming Chiang, James L. Manley, David A. Boothman

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4996-5006
Number of pages11
JournalNucleic acids research
Volume42
Issue number8
DOIs
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Genetics

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