TY - JOUR
T1 - RNase H and Multiple RNA Biogenesis Factors Cooperate to Prevent RNA:DNA Hybrids from Generating Genome Instability
AU - Wahba, Lamia
AU - Amon, Jeremy D.
AU - Koshland, Douglas
AU - Vuica-Ross, Milena
N1 - Funding Information:
We thank Bradley Cairns for generously providing us with an aliquot of the RNA:DNA hybrid antibody. We would also like to thank Chen-ming Fan, Fred Tan, Vincent Guacci, Hugo Tapia, Aaron Welch, Thomas Eng, and Anjali Krishnan for constructive comments on the manuscript. We thank members of the Koshland lab for technical assistance and helpful discussions. This work is supported by a grant to D.K. from Howard Hughes Medical Institution. M.V.-R. was funded by a Richard Starr Ross Clinician Scientist Award.
PY - 2011/12/23
Y1 - 2011/12/23
N2 - Genome instability, a hallmark of cancer progression, is thought to arise through DNA double strand breaks (DSBs). Studies in yeast and mammalian cells have shown that DSBs and instability can occur through RNA:DNA hybrids generated by defects in RNA elongation and splicing. We report that in yeast hybrids naturally form at many loci in wild-type cells, likely due to transcriptional errors, but are removed by two evolutionarily conserved RNase H enzymes. Mutants defective in transcriptional repression, RNA export and RNA degradation show increased hybrid formation and associated genome instability. One mutant, sin3Δ, changes the genome profile of hybrids, enhancing formation at ribosomal DNA. Hybrids likely induce damage in G1, S and G2/M as assayed by Rad52 foci. In summary, RNA:DNA hybrids are a potent source for changing genome structure. By preventing their formation and accumulation, multiple RNA biogenesis factors and RNase H act as guardians of the genome.
AB - Genome instability, a hallmark of cancer progression, is thought to arise through DNA double strand breaks (DSBs). Studies in yeast and mammalian cells have shown that DSBs and instability can occur through RNA:DNA hybrids generated by defects in RNA elongation and splicing. We report that in yeast hybrids naturally form at many loci in wild-type cells, likely due to transcriptional errors, but are removed by two evolutionarily conserved RNase H enzymes. Mutants defective in transcriptional repression, RNA export and RNA degradation show increased hybrid formation and associated genome instability. One mutant, sin3Δ, changes the genome profile of hybrids, enhancing formation at ribosomal DNA. Hybrids likely induce damage in G1, S and G2/M as assayed by Rad52 foci. In summary, RNA:DNA hybrids are a potent source for changing genome structure. By preventing their formation and accumulation, multiple RNA biogenesis factors and RNase H act as guardians of the genome.
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U2 - 10.1016/j.molcel.2011.10.017
DO - 10.1016/j.molcel.2011.10.017
M3 - Article
C2 - 22195970
AN - SCOPUS:84255177502
SN - 1097-2765
VL - 44
SP - 978
EP - 988
JO - Molecular cell
JF - Molecular cell
IS - 6
ER -