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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    ABSTRACT: It is increasingly clear that castration resistant prostate cancer is dependent on the androgen receptor. This has led to the use of anti-androgen therapies that reduce endogenous steroid hormone production as well as the use of androgen receptor antagonists. However, the androgen receptor does not act in isolation and integrates with a milieu of cell signaling proteins to affect cell biology. It is well established that cancer is a genetic disease resulting from the accumulation of mutations and chromosomal translocations that enables cancer cells to survive, proliferate, and disseminate. To maintain genomic integrity, there exists conserved checkpoint signaling pathways to facilitate cell cycle delay, DNA repair, and/or apoptosis in response to DNA damage. The androgen receptor interacts with, affects, and is affected by these DNA damage response proteins. This review will focus on the connections between checkpoint signaling and the androgen receptor in prostate cancer. We will describe what is known about how components of checkpoint signaling regulate androgen receptor activity and what questions still face the field.
    Endocrine Related Cancer 08/2014; 21(5). DOI:10.1530/ERC-14-0217 · 4.81 Impact Factor
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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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    ABSTRACT: Genomic DNA is constantly challenged from endogenous as well as exogenous sources. The DNA damage response (DDR) mechanism has evolved to combat these challenges and ensure genomic integrity. In this review, we will focus on repair of DNA double-strand breaks (DSB) by homologous recombination and the role of several nucleases and other recombination factors as suitable targets for cancer therapy. Their inactivation as well as overexpression have been shown to sensitize cancer cells by increasing toxicity to DNA-damaging agents and radiation or to be responsible for resistance of cancer cells. These factors can also be used in targeted cancer therapy by taking advantage of specific genetic abnormalities of cancer cells that are not present in normal cells and that result in cancer cell lethality.
    FEBS Letters 06/2014; 588(15). DOI:10.1016/j.febslet.2014.06.010 · 3.17 Impact Factor
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    • "Therefore, different systems, based on the use of intrachromosomal substrates containing cleavage sites for the meganuclease I-SceI, have been studied. Notably, these experiments facilitated the characterization of A-EJ at a precise molecular level in the context of chromosomes in living cells [1], [2], [11], [21], [23], [54], [55]. The conclusions drawn from these studies (see below) were confirmed in vivo in mice in the context of physiological processes, such as class switch or V(D)J recombination [5], [10]. "
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    ABSTRACT: DNA double-strand breaks (DSBs) are harmful lesions leading to genomic instability or diversity. Non-homologous end-joining (NHEJ) is a prominent DSB repair pathway, which has long been considered to be error-prone. However, recent data have pointed to the intrinsic precision of NHEJ. Three reasons can account for the apparent fallibility of NHEJ: 1) the existence of a highly error-prone alternative end-joining process; 2) the adaptability of canonical C-NHEJ (Ku- and Xrcc4/ligase IV-dependent) to imperfect complementary ends; and 3) the requirement to first process chemically incompatible DNA ends that cannot be ligated directly. Thus, C-NHEJ is conservative but adaptable, and the accuracy of the repair is dictated by the structure of the DNA ends rather than by the C-NHEJ machinery. We present data from different organisms that describe the conservative/versatile properties of C-NHEJ. The advantages of the adaptability/versatility of C-NHEJ are discussed for the development of the immune repertoire and the resistance to ionizing radiation, especially at low doses, and for targeted genome manipulation.
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