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PLoS Genet. 2017 Dec 27;13(12):e1007136. doi: 10.1371/journal.pgen.1007136. eCollection 2017 Dec.

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

Author information

1
Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Avda. Americo Vespucio 24, Seville, Spain.
2
Institute of Molecular Biology (IMB), Mainz, Germany.
3
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany.
4
Department of Biology, University of Copenhagen, Ole Maaloeesvej 5, Copenhagen N, Denmark.
5
Institute of Neurobiology and Developmental Biology, JGU Mainz, Mainz, Germany.

Abstract

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.

PMID:
29281624
PMCID:
PMC5760084
DOI:
10.1371/journal.pgen.1007136
[Indexed for MEDLINE]
Free PMC Article

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