Mechanisms and regulation of DNA end resection - PubMed (original) (raw)
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Mechanisms and regulation of DNA end resection
Maria Pia Longhese et al. EMBO J. 2010.
Abstract
DNA double-strand breaks (DSBs) are highly hazardous for genome integrity, because failure to repair these lesions can lead to genomic instability. DSBs can arise accidentally at unpredictable locations into the genome, but they are also normal intermediates in meiotic recombination. Moreover, the natural ends of linear chromosomes resemble DSBs. Although intrachromosomal DNA breaks are potent stimulators of the DNA damage response, the natural ends of linear chromosomes are packaged into protective structures called telomeres that suppress DNA repair/recombination activities. Although DSBs and telomeres are functionally different, they both undergo 5'-3' nucleolytic degradation of DNA ends, a process known as resection. The resulting 3'-single-stranded DNA overhangs enable repair of DSBs by homologous recombination (HR), whereas they allow the action of telomerase at telomeres. The molecular activities required for DSB and telomere end resection are similar, indicating that the initial steps of HR and telomerase-mediated elongation are related. Resection of both DSBs and telomeres must be tightly regulated in time and space to ensure genome stability and cell survival.
Conflict of interest statement
The authors declare that they have no conflict of interest.
Figures
Figure 1
DNA end resection at DSBs and telomeres. (A) DSBs in mitotic cells are detected by both MRX and Sae2. Upon phosphorylation of Sae2 by Cdk1, MRX and Sae2 catalyse the initial processing of the 5′ strand, resulting in generation of short ssDNA stretches. The 5′ strand can be substrate for further nucleolytic resection by the concerted action of a helicase, Sgs1, and two nucleases, Exo1 and Dna2. (B) Spo11, MRX and other proteins catalyse the formation of a meiosis-specific DSB. Upon phosphorylation of Sae2 by Cdk1, MRX and Sae2 catalyse the removal of Spo11 by endonucleolytic cleavage. Spo11 removal allows the processing of the 5′ strand by either Exo1 or Dna2–Sgs1. (C) Telomere DNA replication is expected to leave a short 3′ overhang on the lagging strand (upon RNA primer removal) and a blunt end on the leading strand. End processing at the leading-strand telomere can then be initiated by Sae2/MRX, with Sae2 activity requiring Cdk1-mediated phosphorylation. Sgs1 and Exo1 can provide compensatory activities to resect the 5′ C-strand, with Sgs1 acting in conjunction with Dna2.
Figure 2
Regulation of 5′ resection at mitotic DSBs and telomeres. (A) The MRX complex and Ku almost simultaneously bind the DSB ends. In G1, Ku and MRX mediate recruitment of the NHEJ proteins (Lif1, Dnl4 and Nej1), which allow religation of the DSB ends. Recognition of the DSB by MRX also leads to Tel1 recruitment. Both Ku and the NHEJ proteins prevent initiation of resection. In the absence of Ku or NHEJ, the DSB undergoes MRX-dependent resection even in the absence of Cdk1. When the DSB ends are not bound by MRX, Ku also prevents Exo1-mediated resection. In S/G2, Sae2 is activated by Cdk1- and Tel1-dependent phosphorylation events. MRX and Sae2 then catalyse the initial processing of the 5′ strand possibly by endonucleolytic cleavage, which reduces the ability of Ku to bind the ends and promotes extensive 5′ strand resection by Sgs1, Exo1 and Dna2. The 3′-ended ssDNA tails coated by RPA allow recruitment of Mec1, which in turn phosphorylates Sae2, thus contributing to potentiate resection. Mec1 association to DSB ends also leads to DNA damage checkpoint activation. (B) In G1, Rap1, Rif1 and Rif2 mainly act by inhibiting MRX access, whereas Ku protects telomeres from Exo1. As Rap1, Rif1 and Rif2 still prevent MRX action in _yku70_Δ G1 cells, Ku may protect G1 telomeres also from MRX. The lack of telomeric ssDNA should prevent telomerase action. In S/G2, only Rap1, Rif2 and Rif1 still exert their inhibitory effects on telomere processing, but telomere resection can take place because Cdk1 activates Sae2-MRX, which in turn relieves the inhibitory effect of Ku. The resulting telomeric ssDNA is covered by Cdc13, which suppresses DNA damage checkpoint activation and allows telomerase action. If the shelterin-like proteins and/or Ku also regulate Sgs1 and Dna2 activities is still unknown.
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