A central control hub in DNA damage responses: function and regulation of the RBR module

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DNA damage represents a critical threat to every cell in all organisms. Globally, the DNA Damage Response (DDR) consists of a set of tightly regulated events, from sensing of the inflicted damage, activation of a DDR signalling cascade that also blocks cell cycle progression, accumulation of DNA repair factors at the damaged site, to the physical repair of the lesion and/or the replacement of damaged cells. Remarkably, plants can cope with very high concentrations of harmful agents in comparison to animals. Despite this apparent power and their relevance for agriculture under changing environmental conditions, the plant DNA repair pathways are not very well understood. Moreover, the canonical response pathways of yeast and animals appear to be only partially conserved raising the question of how plants can so efficiently repair DNA damage and which regulators are employed in this process. In this context, the preparatory work of both partners has revealed a DDR network relying on the Arabidopsis pRb homolog, called RETINOBLASTOMA RELATED 1 (RBR1). RBR1 appears to function in at least two ways: first, as a transcriptional regulator of DDR genes and second, as a potential assembly factor of repair complexes at the lesion sites. Thus, RBR1 acts as a central control hub in DDR and hence offers a unique starting point to get mechanistic insights into the DDR of plants. Following up on the genome-wide identification of RBR1 binding sites and the proteome-wide protein-protein interaction network of RBR1 under DNA damaging conditions, an aim of this project is to combine the complementary expertise of both partners to understand the molecular mechanism of how targets of RBR1 are controlled upon DNA damage and explore the function of unknown DDR related RBR1 target genes. At the same time, we will investigate how RBR1 itself is regulated upon DNA damage. Since the preparatory work of both partners indicated a prominent role of proteolytic regulation for both the RBR1 functional complex(es) as well as several of its target genes, special emphasis is put on this aspect. To that end, and supported by extensive preparatory data, we follow the hypothesis that the F-box protein FBL17, previously identified in collaborative effort of the two partners, plays a central role in RBR1 homeostasis and might be also involved in selective degradation of RBR1 targets involved in DDR.