DNA double-strand break end resection: a critical relay point for determining the pathway of repair and signaling

Abstract

A DNA double-strand break (DSB) is considered the most critical DNA lesion because it causes cell death and severe mutations if it is not repaired or repaired incorrectly. Accumulating evidence has shown that the majority of DSBs are repaired by DNA non-homologous end joining (NHEJ), the first utilized repair pathway in human cells. In contrast, the repair pathway is sometimes diverted into using homologous recombination (HR), which has increased precision under specific circumstances: e.g., when DSBs are generated at transcriptionally active loci or are not readily repaired due to the complexity of damage at the DSB ends or due to highly compacted chromatin. DSB end resection (resection) is considered the most critical turning point for directing repair towards HR. After resection, the HR process is finalized by RAD51 loading and recombination. Thus, understanding the process of resection is critically important to understand the regulation of the choice of DSB repair pathway. In addition, resection is also an important factor influencing DNA damage signaling because unresected ends preferentially activate ATM, whereas longer resected ends activate ATR. Thus, DSB end resection is a key relay point that determines the repair pathway and the signal balance. In this review, we summarize the mechanism underlying DSB end resection and further discuss how it is involved in cancer therapy.

Funding

Takeda Science Foundation

Suntory Foundation

Sumitomo Foundation

Program of the Network type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University, and Fukushima Medical University

Japan Society for the Promotion of Science(JP17H04713)