Defining transcription stress and the effect it has on genome stability


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Diana Zatreanu1,Jesper Svejstrup1
1The Francis Crick Institute

Abstract

Background

Coordination of DNA-associated processes, including transcription, replication, and repair, is essential to maintain genomic stability. Genome instability has been shown to be one of the driving forces in tumorgenesis. Recent studies have revealed that stalling or arrest of RNAPII transcription complexes, also known as transcription stress, can result in genome instability.  Stalled elongation complexes undergo backtracking followed by cleavage of the 3’ end of the nascent strand in a manner that is dependent on TFIIS. In yeast, co-mutating two amino acids in the acidic loop of TFIIS, D290 and E291 inhibits the intrinsic ability of RNAPII to perform transcript cleavage thus impeding rescue of polymerase molecules experiencing transcription stress.

Method

We investigated if the highly similar human homologue of TFIIS, TCEA1, has the same function and use the TFIIS double point mutant (DE/AA-TCEA1) as a model of transcription stress. To understand the role TCEA1 plays in  suppressing transcription-associated genome instability, I used genome-wide approaches that map the RNAPII density landscape over genes, as well as the nascent RNA production.

Results

Our results showed that by co-mutating the two amino acids D282 and E283 in the human homolog TCEA1, gives rise to a similar phenotype as seen in yeast. Mutant TCEA1 expressing cells have an impaired growth; they have an increased polyubiquitilation of RNAPII, a hallmark of transcription stalling/stress and are slower transcribing. Thus the DE/AA-TCEA1 expressing cells are the perfect tool to study transcription stress in vivo.

Conclusion

My results shed light on the role played by the human TFIIS homolog in vivo, and whether its activity is important for maintaining transcription stress related-genome stability.

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