Figure 6. A model for resection initiation at clean or blocked DSBs. DNA end resection at a blocked DSB with protein or chemical adducts (denoted by pink rectangle) is initiated through endocleavage by the MRN nuclease in conjunction with CtIP, with the nuclease activity of MRN being responsible for the cleavage. By contrast, resection initiation at a clean DSB with free DNA ends is initiated by Dna2, which cleaves the 5′ strand DNA ∼10–20 nts away from the end. The MRN complex promotes this step by facilitating the recruitment of Dna2 to the DNA end. In the absence of Dna2, CtIP–MRN mediate an alternative pathway of resection initiation, with the endonuclease activity of MRN cleaving the 5′ strand DNA ≥45 nts away from the end. Both Dna2 and CtIP–MRN pathways of resection initiation apparently require DNA helicases such as WRN, BLM, RECQL4 and likely Dna2, which unwind DNA ends to generate ssDNA for cleavages. The ssDNA-binding protein RPA binds the resulting ssDNA and promotes resection initiation by both pathways. Dna2-mediated end cleavage requires the direct interaction between Dna2 and the N-terminus of RPA1 in the RPA complex, but this domain of RPA1 is dispensable for the CtIP–MRN pathway of resection initiation.
Image published in: Paudyal SC et al. (2017)
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