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

Nucleic Acids Research (Impact Factor: 9.11). 03/2014; 42(8). DOI: 10.1093/nar/gku160
Source: PubMed


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.

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Available from: Julio C. Morales, Mar 05, 2014
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    • "Alterations in K-H copy number, single nucleotide polymorphisms (SNPs) and methylation-related changes in K-H protein levels could matter, since one copy number loss of K-H in the K-H +/-mice correlated with 50% less protein levels in the at-risk tissues of mice, and this constituted carcinogenic risk. For therapy, loss of K-H correlates with hypersensitivity to agents that induce DSBs and are used for cancer therapies, including IR, cisplatin, and topoisomerase I/II poisons (Morales et al., 2014). "
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