Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress

REV3, the catalytic subunit of translesion polymerase zeta (polζ), is commonly associated with DNA damage bypass and repair. Despite sharing accessory subunits with replicative polymerase δ, very little is known about the role of polζ in DNA replication. We previously demonstrated that inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells. To reveal determinants of this sensitivity and obtain insights into the cellular function of REV3, we performed whole human genome RNAi library screens aimed at identification of synthetic lethal interactions with REV3 in A549 lung cancer cells. The top confirmed hit was RRM1, the large subunit of ribonucleotide reductase (RNR), a critical enzyme of de novo nucleotide synthesis. Treatment with the RNR-inhibitor hydroxyurea (HU) synergistically increased the fraction of REV3-deficient cells containing single stranded DNA (ssDNA) as indicated by an increase in replication protein A (RPA). However, this increase was not accompanied by accumulation of the DNA damage marker γH2AX suggesting a role of REV3 in counteracting HU-induced replication stress (RS). Consistent with a role of REV3 in DNA replication, increased RPA staining was confined to HU-treated S-phase cells. Additionally, we found genes related to RS to be significantly enriched among the top hits of the synthetic sickness/lethality (SSL) screen further corroborating the importance of REV3 for DNA replication under conditions of RS.

Einführung zu den Dialogtexten Altkatholische Kirchen der Utrechter Union – Mar Thoma Syrian Church of Malabar

2011 bis 2014 arbeitete eine gemischte Dialogkommission der Altkatholischen Kirchen der Utrechter Union und der Mar Thoma Syrian Church of Malabar. Sie erarbeitete drei Erklärungen zu Handen der Bischofskonferenzen der beiden Kirchen. Der vorliegende Beitrag bildet eine Einführung in diese Erklärungen aus christkatholischer Sicht. Er wird der Nationalsynode der Christkatholischen Kirche der Schweiz, die im Juni 2015 tagt, vorgelegt, und ggf. im WWW veröffentlicht.