The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage
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The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage. / Lafuente-Barquero, Juan; Luke-Glaser, Sarah; Graf, Marco; Pinela da Silva, Sonia Cristina; Gómez-González, Belén; Lockhart, Arianna; Lisby, Michael; Aguilera, Andrés; Luke, Brian.
I: PLOS Genetics, Bind 13, Nr. 12, e1007136, 27.12.2017.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage
AU - Lafuente-Barquero, Juan
AU - Luke-Glaser, Sarah
AU - Graf, Marco
AU - Pinela da Silva, Sonia Cristina
AU - Gómez-González, Belén
AU - Lockhart, Arianna
AU - Lisby, Michael
AU - Aguilera, Andrés
AU - Luke, Brian
PY - 2017/12/27
Y1 - 2017/12/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85039978090&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1007136
DO - 10.1371/journal.pgen.1007136
M3 - Journal article
C2 - 29281624
AN - SCOPUS:85039978090
VL - 13
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 12
M1 - e1007136
ER -
ID: 188270518