Abstract
DNA end resection has a key role in double-strand break repair and DNA replication. Defective DNA end resection can cause malfunctions in DNA repair and replication, leading to greater genomic instability. DNA end resection is initiated by MRN-CtIP generating short, 3′-single-stranded DNA (ssDNA). This newly generated ssDNA is further elongated by multiple nucleases and DNA helicases, such as EXO1, DNA2, and BLM. Effective DNA end resection is essential for error-free homologous recombination DNA repair, the degradation of incorrectly replicated DNA and double-strand break repair choice. Because of its importance in DNA repair, DNA end resection is strictly regulated. Numerous mechanisms have been reported to regulate the initiation, extension, and termination of DNA end resection. Here, we review the general process of DNA end resection and its role in DNA replication and repair pathway choice.
Highlights
DNA double-strand breaks (DSBs) are seriously harmful genomic lesions that threaten genomic stability and cell survival
We summarize the general process of DNA end resection and highlight the function of DNA end resection in DNA replication and DSB repair pathway choice
MRE11 endonuclease associated with RAD50, NBS1, and phosphorylated CtBP-interacting protein (CtIP) preferentially generates a short 3′-single-stranded DNA (ssDNA) overhang, which is indispensable for extensive DNA end resection and RPA complex loading (Fig. 1a)[18,27]
Summary
The MRN complex consists of three subunits, MRE11, RAD50, and Nibrin (NBS1) All of these components are established regulators of DNA damage signal transduction and DNA end resection initiation. MRE11 exhibits both 3′–5′ exonuclease and endonuclease activity in vitro Both the endonuclease and exonuclease activity of MRE11 have been shown to be important for DNA end resection. The C-terminal domain is important for ATM recruitment[10,22,23] These characteristics make NBS1 absolutely indispensable in the mammalian system, which differ from that in yeast where the Xrs2/NBS1 subunit is not required for end resection reaction in vitro[24]. MRE11 endonuclease associated with RAD50, NBS1, and phosphorylated CtIP preferentially generates a short 3′-ssDNA overhang, which is indispensable for extensive DNA end resection and RPA complex loading (Fig. 1a)[18,27]
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