Cell cycle regulation of homologous recombination inSaccharomyces cerevisiae

Abstract

Homologous recombination (HR) contributes to maintaining genome integrity by facilitating error-free repair of DNA double-strand breaks (DSBs) primarily during the S and G2 phases of the mitotic cell cycle, while nonhomologous end joining (NHEJ) is the preferred pathway for DSB repair in G1 phase. The decision to repair a DSB by NHEJ or HR is made primarily at the level of DSB end resection, which is inhibited by the Ku complex in G1 and promoted by the Sae2 and Mre11 nucleases in S/G2 . The cell cycle regulation of HR is accomplished both at the transcription level and at the protein level through post-translational modification, degradation and subcellular localization. Cyclin-dependent kinase Cdc28 plays an established key role in these events, while the role of transcriptional regulation and protein degradation are less well understood. Here, the cell cycle regulatory mechanisms for mitotic HR in Saccharomyces cerevisiae are reviewed, and evolutionarily conserved principles are highlighted.

Disruption of SUMO-targeted ubiquitin ligases Slx5–Slx8/RNF4 alters RecQ-like helicase Sgs1/BLM localization in yeast and human cells

“…Furthermore, the percentage of cells with an Sgs1 focus is significantly decreased in G1 and does not increase following IR treatment (Figure 2B, p > 0.1). These results are consistent with the notion that HR is repressed during G1, since a homologous template is unavailable for repair [52]. Accordingly, Rad52 foci are also repressed during a G1 arrest and similarly do not respond to irradiation (Figure 2A, C; p > 0.1).…”

Mechanisms and Regulation of Mitotic Recombination in Saccharomyces cerevisiae

“…DNA damage-induced genes with relevance to mitotic recombination are the ribonucleotide reductase genes RNR1–4 , which are required for reduction of ribonucleotides to their corresponding 2′-deoxyribonucleotides (dNTPs) necessary for DNA synthesis during recombination, the DNA damage checkpoint genes RAD53 and MEC1 , which form a positive feedback loop to increase their own expression, and the recombination genes RFA1 , RFA2 , RFA3 , RAD50 , SRS2 , RAD54 , and RAD51 which are also induced in a MEC1 -dependent manner (Cole et al 1987; Elledge and Davis, 1989, 1990; Yagle and McEntee 1990; Basile et al 1992; Kiser and Weinert 1996; Jelinsky and Samson 1999; Vallen and Cross 1999; Gasch et al 2001; Mercier et al 2001; Benton et al 2006) (reviewed in Fu et al 2008). In addition, many recombination genes exhibit cell cycle regulated expression, which peaks in late G1 to early S phase (Basile et al 1992; Spellman et al 1998 and reviewed in Mathiasen and Lisby 2014), although the functional importance of this regulation remains to be determined.…”

Regulation of Rad6/Rad18 Activity During DNA Damage Tolerance

“…HR can also rescue replication forks arrested at small DNA adducts, but it may be more harmful than good in such cases, as the process can trigger cell cycle arrest, and failed attempts can lead to gross chromosomal rearrangements. Indeed, eukaryotic cells have established a temporal hierarchy to avoid such disasters: The Rad6/Rad18-mediated pathways are elicited first at replication-blocking lesions, whereas HR serves as a so-called salvage pathway and is summoned only when the other pathways are malfunctioning (61, 79). In S. cerevisiae , conjugation of SUMO (small ubiquitin-like modifier) to PCNA proctors this hierarchy.…”