Abstract
Replication forks stall at different DNA obstacles such as those originated by transcription. Fork stalling can lead to DNA double-strand breaks (DSBs) that will be preferentially repaired by homologous recombination when the sister chromatid is available. The Rrm3 helicase is a replisome component that promotes replication upon fork stalling, accumulates at highly transcribed regions and prevents not only transcription-induced replication fork stalling but also transcription-associated hyper-recombination. This led us to explore the possible role of Rrm3 in the repair of DSBs when originating at the passage of the replication fork. Using a mini-HO system that induces mainly single-stranded DNA breaks, we show that rrm3Δ cells are defective in DSB repair. The defect is clearly seen in sister chromatid recombination, the major repair pathway of replication-born DSBs. Our results indicate that Rrm3 recruitment to replication-born DSBs is crucial for viability, uncovering a new role for Rrm3 in the repair of broken replication forks.
Highlights
Genetic instability is a hallmark of cancer cells [1]
Different DNA obstacles, such as those originated by transcription, frequently hamper replication fork progression leading to fork stalling or even fork breakage
Rrm3Δ cells show a defect in the recombination with the sister chromatid, the preferred template for the maintenance of genome integrity
Summary
In the last few decades, evidence has shown that replication is one main source of genetic instability. If a stalled RF is processed by endonuclease cleavage or if the replisome encounters a nick or single stranded DNA gap, it can give rise to DNA double-strand breaks (DSBs), one of the most cytotoxic DNA lesions. DSBs can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR), which is used preferentially in the S/G2 phases of the cell cycle when the sister chromatid is available. Specific factors have been involved in the choice of the sister chromatid as the template for the repair of replication-born DSBs, such as the Smc complex [5, 6] or the acetylation state of Histone H3 lysine 56 residue [7]
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