The RecQ4 Orthologue Hrq1 Is Critical for DNA Interstrand Cross-Link Repair and Genome Stability in Fission Yeast

Abstract

Of the five human RecQ family helicases, RecQ4, BLM, and WRN suppress distinct genome instability-linked diseases with severe phenotypes, often with indeterminate etiologies. Here, we functionally define Hrq1, a novel orthologue of RecQ4 from fission yeast. Biochemical analysis of Hrq1 reveals a DEAH box- and ATP-dependent 3′-5′ helicase activity on various DNA substrates, including bubbles but not blunt duplexes, characteristic of the RecQ family. Cells lacking Hrq1 suffer spontaneous genomic instability and, consequently, require homologous recombination repair and the DNA damage checkpoint for viability. Hrq1 supports the nucleotide excision repair of DNA damage caused by the chemotherapeutic agent cisplatin and, in certain genetic contexts, UV light. Genetic epistasis analyses reveal that Hrq1 acts parallel to the PCNA/Ubc13/Mms2-dependent postreplication repair (PRR) pathway. Thus, in hrq1Δ cells, lesions are channeled through the PRR pathway, yielding hyperrecombinant and mutator phenotypes; analogous defects may underlie the genetic instability and diseases associated with RecQ4 dysfunction.

ACKNOWLEDGMENTS

M.N.B. is supported by a Scholar Award from the Leukemia & Lymphoma Society. This study was funded by NIH grants GM068608 and GM081840 awarded to M.N.B.

We thank Alan Lehman (University of Sussex) and Matthew Whitby (Oxford University) for providing strains used in this study.