Role of mammalian Mre11 in classical and alternative nonhomologous end joining

Harvard University, Cambridge, Massachusetts, United States
Nature Structural & Molecular Biology (Impact Factor: 13.31). 09/2009; 16(8):814-8. DOI: 10.1038/nsmb.1640
Source: PubMed


The mammalian Mre11-Rad50-Nbs1 (MRN) complex coordinates double-strand break signaling with repair by homologous recombination and is associated with the H2A.X chromatin response to double-strand breaks, but its role in nonhomologous end joining (NHEJ) is less clear. Here we show that Mre11 promotes efficient NHEJ in both wild-type and Xrcc4(-/-) mouse embryonic stem cells. Depletion of Mre11 reduces the use of microhomology during NHEJ in Xrcc4(+/+) cells and suppresses end resection in Xrcc4(-/-) cells, revealing specific roles for Mre11 in both classical and alternative NHEJ. The NHEJ function of Mre11 is independent of H2A.X. We propose a model in which both enzymatic and scaffolding functions of Mre11 cooperate to support mammalian NHEJ.

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    • "While the factors involved and mechanism underlying aNHEJ are poorly understood, both poly (ADP-ribose) polymerase 1 (PARP1) and the MRN (MRE11, RAD50, NBS1) complex appear to play key roles. Recent work has linked the MRN complex to the process of end resection and PARP1 to join at telomeres lacking the Ku heterodimer (Haince et al. 2008, Deriano et al. 2009, Rass et al. 2009, Xie et al. 2009, Sfeir & de Lange 2012). Further studies need to be performed to determine whether aNHEJ operates as an independent repair pathway. "
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    • "Interestingly, structural integrity of the complex is more important for the end resection than for its nuclease activity. MRE11's nuclease activity together with NBS1 is nevertheless required for MMEJ, and it also uses its endonuclease activity to cleave a covalently bound SPO11 at the 5 0 -ends of the DNA after DSB formation during meiosis to initiate their resection [128] [129] [130] [131]. In addition, the MRN complex localizes to the telomeres and regulates telomeric length either by recruitment of the telomerase RNA subunit or as a sensor of damaged telomeres promoting ATM activation and alternative lengthening of telomeres [132] [133] [134]. "
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