Orchestration and organization of recombinational repair: Roles of the Slx5-8 complex, the Srs2 antirecombinase, and the Rad54 and Rdh54 proteins

The avoidance of mutation and genome aberration is critical to maintaining the integrity of genomic DNA, and in prevention of cancer and chromosomal abnormalities. Thus, it is a high priority of the cell to respond appropriately to DNA damage. To contend with DNA damage, cells elicit a multi-faceted response: the cell cycle is halted to prevent chromosome segregation while the DNA is repaired, and repair pathways are initiated to heal the lesion and restore the genome. To deal with the scores of different types of DNA damage, the cell has an arsenal of repair pathways at its disposal. In addition, the cell has to integrate information from many different sources into order to make the most suitable choice for which repair pathway to engage. The decision-making process is elaborate and its intricacies are still being revealed. In particular it is becoming clear that this process is not an all-or-nothing approach and that the cell may engage several repair pathways before committing to a course of action. In this work, we describe several mechanisms that are involved in the decision-making process, and one recurring theme of this work are the dynamics of repair complexes required for the proper function of repair pathways. Instability through the dynamics of repair complexes likely involves protein turnover and the Slx5-8 enzyme is involved in pathway choice by modulating protein modification and turnover of complexes. Direct disassembly of repair complexes has been demonstrated for the Srs2 protein, which translocates along DNA and can strip away bound protein. This activity is proposed to maintain stringent conditions for initiation of the recombinational repair pathways. Disassembly of repair complexes by the Rad54 protein is also important for the proper completion of repair pathways and subsequent re-entry into the cell cycle. In addition, protein disassembly and remodeling at the site of chromosomal attachment by the Rdh54 protein may facilitate cell division after repair is deemed successful. Although they must necessarily be studied separately, these processes do not occur in isolation. All these factors likely work in concert to guide repair pathways and maintain the stringent conditions necessary for high-fidelity repair and maintenance of the genome.