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Molecular and Cellular Biology, April 2006, p. 3327-3334, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3327-3334.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Replication Fork Progression Is Impaired by Transcription in Hyperrecombinant Yeast Cells Lacking a Functional THO Complex

Ralf E. Wellinger, Félix Prado, and Andrés Aguilera*

Departamento de Genética, Facultad de Biologia, Universidad de Sevilla, Sevilla, Spain

Received 19 October 2005/ Returned for modification 22 November 2005/ Accepted 25 January 2006

THO/TREX is a conserved, eukaryotic protein complex operating at the interface between transcription and messenger ribonucleoprotein (mRNP) metabolism. THO mutations impair transcription and lead to increased transcription-associated recombination (TAR). These phenotypes are dependent on the nascent mRNA; however, the molecular mechanism by which impaired mRNP biogenesis triggers recombination in THO/TREX mutants is unknown. In this study, we provide evidence that deficient mRNP biogenesis causes slowdown or pausing of the replication fork in hpr1{Delta} mutants. Impaired replication appears to depend on sequence-specific features since it was observed upon activation of lacZ but not leu2 transcription. Replication fork progression could be partially restored by hammerhead ribozyme-guided self-cleavage of the nascent mRNA. Additionally, hpr1{Delta} increased the number of S-phase but not G2-dependent TAR events as well as the number of budded cells containing Rad52 repair foci. Our results link transcription-dependent genomic instability in THO mutants with impaired replication fork progression, suggesting a molecular basis for a connection between inefficient mRNP biogenesis and genetic instability.

* Corresponding author. Mailing address: Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Avda. Reina Mercedes 6, 41012 Sevilla, Spain. Phone: (34) 954557107. Fax: (34) 954557104. E-mail: aguilo{at}us.es.

Molecular and Cellular Biology, April 2006, p. 3327-3334, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3327-3334.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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