Article open access publication

The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage

PLOS Genetics, Public Library of Science (PLoS), ISSN 1553-7390

Volume 13, 12, 2017

DOI:10.1371/journal.pgen.1007136, Dimensions: pub.1100087641, PMC: PMC5760084, PMID: 29281624,

Affiliations

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  1. (1) Andalusian Molecular Biology and Regenerative Medicine Centre, grid.427489.4
  2. (2) Institute of Molecular Biology, grid.424631.6
  3. (3) Heidelberg University, grid.7700.0
  4. (4) University of Copenhagen, grid.5254.6, KU
  5. (5) Institute of Neurobiology and Developmental Biology, JGU Mainz, Mainz, Germany

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Germany

Denmark

Spain

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Europe

Description

RNA-DNA hybrids are naturally occurring obstacles that must be overcome by the DNA replication machinery. In the absence of RNase H enzymes, RNA-DNA hybrids accumulate, resulting in replication stress, DNA damage and compromised genomic integrity. We demonstrate that Mph1, the yeast homolog of Fanconi anemia protein M (FANCM), is required for cell viability in the absence of RNase H enzymes. The integrity of the Mph1 helicase domain is crucial to prevent the accumulation of RNA-DNA hybrids and RNA-DNA hybrid-dependent DNA damage, as determined by Rad52 foci. Mph1 forms foci when RNA-DNA hybrids accumulate, e.g. in RNase H or THO-complex mutants and at short telomeres. Mph1, however is a double-edged sword, whose action at hybrids must be regulated by the Smc5/6 complex. This is underlined by the observation that simultaneous inactivation of RNase H2 and Smc5/6 results in Mph1-dependent synthetic lethality, which is likely due to an accumulation of toxic recombination intermediates. The data presented here support a model, where Mph1's helicase activity plays a crucial role in responding to persistent RNA-DNA hybrids.

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Times Cited: 21

Field Citation Ratio (FCR): 4.58

Relative Citation ratio (RCR): 1.27

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