期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：4
DOI：10.1073/pnas.2113871119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Homologous DNA recombination is an essential pathway necessary for the repair of double-stranded DNA breaks. Defects in this pathway are associated with hereditary breast cancer, ovarian cancer, and cancer-prone syndromes. Although essential, too much recombination is also bad and can lead to genetic mutations. Thus, cells have evolved “antirecombinase” enzymes that can actively dismantle recombination intermediates to prevent excessive recombination. However, our current understanding of how antirecombinases are themselves regulated remains very limited. Here, we study the antirecombinase Srs2 and its regulation by the recombination accessory factors Rad54 and Rdh54. Our data suggest that Rad54 and Rdh54 act synergistically to function as key regulators of Srs2, thus serving as “licensing factors” that enable timely progression of DNA repair.
Srs2 is a superfamily 1 (SF1) helicase that participates in several pathways necessary for the repair of damaged DNA. Srs2 regulates formation of early homologous recombination (HR) intermediates by actively removing the recombinase Rad51 from single-stranded DNA (ssDNA). It is not known whether and how Srs2 itself is down-regulated to allow for timely HR progression. Rad54 and Rdh54 are two closely related superfamily 2 (SF2) motor proteins that promote the formation of Rad51-dependent recombination intermediates. Rad54 and Rdh54 bind tightly to Rad51-ssDNA and act downstream of Srs2, suggesting that they may affect the ability of Srs2 to dismantle Rad51 filaments. Here, we used DNA curtains to determine whether Rad54 and Rdh54 alter the ability of Srs2 to disrupt Rad51 filaments. We show that Rad54 and Rdh54 act synergistically to greatly restrict the antirecombinase activity of Srs2. Our findings suggest that Srs2 may be accorded only a limited time window to act and that Rad54 and Rdh54 fulfill a role of prorecombinogenic licensing factors.
