Elsevier

DNA Repair

Volume 11, Issue 10, 1 October 2012, Pages 781-788
DNA Repair

Mini review
From yeast to mammals: Recent advances in genetic control of homologous recombination

https://doi.org/10.1016/j.dnarep.2012.07.001Get rights and content

Abstract

Misregulation of DNA repair is associated with genetic instability and tumorigenesis. To preserve the integrity of the genome, eukaryotic cells have evolved extremely intricate mechanisms for repairing DNA damage. One type of DNA lesion is a double-strand break (DSB), which is highly toxic when unrepaired. Repair of DSBs can occur through multiple mechanisms. Aside from religating the DNA ends, a homologous template can be used for repair in a process called homologous recombination (HR). One key step in committing to HR is the formation of Rad51 filaments, which perform the homology search and strand invasion steps. In S. cerevisiae, Srs2 is a key regulator of Rad51 filament formation and disassembly. In this review, we highlight potential candidates of Srs2 orthologues in human cells, and we discuss recent advances in understanding how Srs2's so-called “anti-recombinase” activity is regulated.

Section snippets

Introduction: overview of DSB repair by HR

Repair of DNA damage is essential to preventing mutations and chromosomal rearrangements. The DNA repair process involves many proteins working together in a tightly regulated system to fix the damage. Double-strand breaks (DSBs) are one of the most lethal types of DNA damage, and can arise from both endogenous (i.e. replicative damage or reactive oxygen species) and exogenous sources (i.e. radon). Cells must repair approximately 50 DSBs per day, which correlates with a frequency of one DSB per

Yeast regulators of Rad51

Rad51 plays a central role in facilitating recombination by performing the homology search and strand invasion steps of HR. Therefore, regulating Rad51 filament formation is important for promoting error-free DNA repair. In yeast, Srs2 is one of the most important antagonists of Rad51, thereby helping to protect the cell from inappropriate HR. Srs2 removes Rad51 from ssDNA ends, thereby preventing the homology search of HR (Fig. 2D)[14]. After strand invasion, Srs2 is unable to disassemble

Regulators of Srs2

The formation of Rad51 filaments is a crucial step for the initiation of HR. There are systems in place that either facilitate this step or negatively regulate it. The balance between assembly and disassembly reactions dictate whether the conditions at the site of repair will favor HR or other repair processes. So far we have covered Srs2 and its functional homologues in humans. These proteins carry out the key functions of negatively regulating Rad51 filament formation both presynaptically and

Conclusions and future directions

Regulation of recombination is critical to prevent genomic instability and chromosomal rearrangements observed in cancer. Commitment to HR, an error-free DNA repair pathway, requires formation of Rad51 filaments. In yeast, Srs2, the DNA helicase “anti-recombinase” removes Rad51 from ssDNA ends, and Mph1 disassembles D-loops. In mammalian cells, there are multiple proteins that perform similar functions. For example, both PARI and RECQL5 can remove RAD51 from ssDNA whereas RTEL can disassemble

Conflict of interest

The authors confirm there is no conflict of interest, financial or otherwise, in this work.

Acknowledgments

We thank Wolf Heyer, Dominique Bratton-Palmer, Cheryl Clauson, Emma Satlof-Bedrick, Stephen Godin, and Faiz Kabbinavar for providing helpful comments and edits to the manuscript. This work is supported by the National Institutes of Health grant R00GM088413 to KAB, the PNC, UPCI Director Distinguished Scholar Award to KAB and the Dean's Summer Research Program at the University of Pittsburgh School of Medicine to YK.

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