期刊
NUCLEIC ACIDS RESEARCH
卷 42, 期 8, 页码 4996-5006出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku160
关键词
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资金
- National Institutes of Health [CA139217, GM28983, CA103867]
- CPRIT [RP110471]
- Welch Foundation [I-1805]
- Cancer Biology T32 training grant [T32CA124334-06]
- NIH [CA139217]
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 gamma-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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