MRN complex

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The MRN complex (MRX complex in yeast) is a protein complex consisting of Mre11, Rad50 and Nbs1 (also known as Nibrin [1] in humans and as Xrs2 in yeast). In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-strand DNA breaks prior to repair by homologous recombination or non-homologous end joining. The MRN complex binds avidly to double-strand breaks both in vitro and in vivo and may serve to tether broken ends prior to repair by non-homologous end joining or to initiate DNA end resection prior to repair by homologous recombination. The MRN complex also participates in activating the checkpoint kinase ATM in response to DNA damage. [2] [3] Production of short single-strand oligonucleotides by Mre11 endonuclease activity has been implicated in ATM activation by the MRN complex. [4]

Contents

Evolutionary ancestry and biologic function

The MRN complex has been mainly studied in eukaryotes. However, recent work shows that two of the three protein components of this complex, Mre11 and Rad50, are also conserved in extant prokaryotic archaea. [5] This finding suggests that key components of the eukaryotic MRN complex are derived by evolutionary descent from the archaea. In the archaeon Sulfolobus acidocaldarius, the Mre11 protein interacts with the Rad50 protein and appears to have an active role in the repair of DNA damages experimentally introduced by gamma radiation. [6] Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks, [7] by a process that likely involves homologous recombination.

Biological function

Repair of double-strand DNA breaks

In eukaryotes, the MRN complex (through cooperation of its subunits) has been identified as a crucial player in many stages of the repair process of double-strand DNA breaks: initial detection of a lesion, halting of the cell cycle to allow for repair, selection of a specific repair pathway (i.e., via homologous recombination or non-homologous end joining) and providing mechanisms for initiating reconstruction of the DNA molecule (primarily via spatial juxtaposition of the ends of broken chromosomes). [8] Initial detection is thought to be controlled by both Nbs1 [9] and MRE11. [10] Likewise, cell cycle checkpoint regulation is ultimately controlled by phosphorylation activity of the ATM kinase, which is pathway dependent on both Nbs1 [11] and MRE11. [10] MRE11 alone is known to contribute to repair pathway selection, [12] while MRE11 and Rad50 work together to spatially align DNA molecules: Rad50 tethers two linear DNA molecules together [13] while MRE11 fine-tunes the alignment by binding to the ends of the broken chromosomes. [14]

Telomere maintenance

Telomeres maintain the integrity of the ends of linear chromosomes during replication and protect them from being recognized as double-strand breaks by the DNA repair machinery. MRN participates in telomere maintenance primarily via association with the TERF2 protein of the shelterin complex. [15] Additional studies have suggested that Nbs1 is a necessary component protein for telomere elongation by telomerase. [16] Additionally, knockdown of MRN has been shown to significantly reduce the length of the G-overhang at human telomere ends, [17] which could inhibit the proper formation of the so-called T-loop, destabilizing the telomere as a whole. Telomere lengthening in cancer cells by the alternative lengthening of telomeres (ALT) mechanism has also been shown to be dependent on MRN, especially on the Nbs1 subunit. [18] Taken together, these studies suggest MRN plays a crucial role in maintenance of both length and integrity of telomeres.

Role in human disease

Mutations in MRE11 have been identified in patients with an ataxia-telangiectasia-like disorder (ATLD). [19] Mutations in RAD50 have been linked to a Nijmegen Breakage Syndrome-like disorder (NBSLD). [20] Mutations in the NBN gene, encoding the human Nbs1 subunit of the MRN complex, are causal for Nijmegen Breakage Syndrome. [21] All three disorders belong to a group of chromosomal instability syndromes that are associated with impaired DNA damage response and increased cellular sensitivity to ionising radiation. [22]

Role in human cancer

The MRN complex's roles in cancer development are as varied as its biological functions. Double-strand DNA breaks, which it monitors and signals for repair, may themselves be the cause of carcinogenic genetic alteration, [23] suggesting MRN provides a protective effect during normal cell homeostasis. However, upregulation of MRN complex sub-units has been documented in certain cancer cell lines when compared to non-malignant somatic cells, [24] suggesting some cancer cells have developed a reliance on MRN overexpression. Since tumor cells have increased mitotic rates compared to non-malignant cells this is not entirely unexpected, as it is plausible that an increased rate of DNA replication necessitates higher nuclear levels of the MRN complex. However, there is mounting evidence that MRN is itself a component of carcinogenesis, metastasis and overall cancer aggression.

Tumorigenesis

In mice models, mutations in the Nbs1 subunit of MRN alone (producing the phenotypic analog of Nijmegen Breakage Syndrome in humans) have failed to produce tumorigenesis. However, double knockout mice with mutated Nbs1 which were also null of the p53 tumor suppressor gene displayed tumor onset significantly earlier than their p53 wildtype controls. [25] This implies that Nbs1 mutations are themselves sufficient for tumorigenesis; a lack of malignancy in the control seems attributable to the activity of p53, not of the benignity of Nbs1 mutations. Extension studies have confirmed an increase in B and T-cell lymphomas in Nbs1-mutated mice in conjunction with p53 suppression, indicating potential p53 inactivation in lymphomagenesis, [26] which occurs more often in NBS patients. [27] [28] Knockdown of MRE11 in various human cancer cell lines has also been associated with a 3-fold increase in the level of p16INK4a tumor suppressor protein, [29] which is capable of inducing cellular senescence and subsequently halting tumor cell proliferation. This is thought primarily to be the result of methylation of the p16INK4 promotor gene by MRE11. These data suggest maintaining the integrity and normal expression levels of MRN provides a protective effect against tumorigenesis.

Metastasis

Suppression of MRE11 expression in genetically engineered human breast (MCF7) and bone (U2OS) cancer cell lines has resulted in decreased migratory capacity of these cells, [29] indicating MRN may facilitate metastatic spread of cancer. Decreased expression of MMP-2 and MMP-3 matrix metalloproteinases, which are known to facilitate invasion and metastasis, [30] occurred concomitantly in these MRE11 knockdown cells. Similarly, overexpression of Nbs1 in human head and neck squamous cell carcinoma (HNSCC) samples has been shown to induce epithelial–mesenchymal transition (EMT), which itself plays a critical role in cancer metastasis. [31] In this same study, Nbs1 levels were significantly higher in secondary tumor samples than in samples from the primary tumor, providing evidence of a positive correlation between metastatic spread of tumor cells and levels of MRN expression. Taken together, these data suggest at least two of the three subunits of MRN play a role in mediating tumor metastasis, likely via an association between overexpressed MRN and both endogenous (EMT transition) and exogenous (ECM structure) cell migratory mechanisms.

Aggression

Cancer cells almost universally possess upregulated telomere maintenance mechanisms [32] which allows for their limitless replicative potential. The MRN complex's biological role in telomere maintenance has prompted research linking MRN to cancer cell immortality. In human HNSCC cell lines, disruption of the Nbs1 gene (which downregulates expression of the entire MRN complex), has resulted in reduced telomere length and persistent lethal DNA damage in these cells. [33] When combined with treatment of PARP (poly (ADP-ribose) polymerase) inhibitor (known as PARPi), these cells showed an even greater reduction in telomere length, arresting tumor cell proliferation both in vitro and in vivo via mouse models grafted with various HNSCC cell lines. While treatment with PARPi alone has been known to induce apoptosis in BRCA mutated cancer cell lines, [34] this study shows that MRN downregulation can sensitize BRCA-proficient cells (those not possessing BRCA mutations) to treatment with PARPi, offering an alternative way to control tumor aggression.

The MRN complex has also been implicated in several pathways contributing to the insensitivity of cancer stem cells to the DNA damaging effects of chemotherapy and radiation treatment, [35] which is a source of overall tumor aggression. Specifically, the MRN inhibitor Mirin (inhibiting MRE11) has been shown to disrupt the ability of ATM kinase to control the G2-M DNA damage checkpoint, which is required for repair of double-strand DNA breaks. [36] The loss of this checkpoint strips cancer stem cells' ability to repair lethal genetic lesions, making them vulnerable to DNA damaging therapeutic agents. Likewise, overexpression of Nbs1 in HNSCC cells has been correlated with increased activation of the PI3K/AKT pathway, which itself has been shown to contribute to tumor aggression by reducing apoptosis. [37] Overall, cancer cells appear to rely on MRN's signaling and repair capabilities in response to DNA damage in order to achieve resistance to modern chemo- and radiation therapies.

See also

Related Research Articles

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Non-homologous end joining</span> Pathway that repairs double-strand breaks in DNA

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.

<span class="mw-page-title-main">ATM serine/threonine kinase</span>

ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

<span class="mw-page-title-main">Nijmegen breakage syndrome</span> Medical condition

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA.

<span class="mw-page-title-main">Ataxia telangiectasia and Rad3 related</span> Protein kinase that detects DNA damage and halts cell division

Serine/threonine-protein kinase ATR, also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1), is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.

<span class="mw-page-title-main">Nibrin</span> Protein-coding gene in the species Homo sapiens

Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.

<span class="mw-page-title-main">H2AFX</span> Histone protein from the H2A family

H2A histone family member X is a type of histone protein from the H2A family encoded by the H2AFX gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.

<span class="mw-page-title-main">MRE11A</span> Protein-coding gene in the species Homo sapiens

Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the MRE11 gene. The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.

<span class="mw-page-title-main">Telomeric repeat-binding factor 2</span> Protein

Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene. It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange, where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.

<span class="mw-page-title-main">Rad50</span> Protein-coding gene in the species Homo sapiens

DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.

<span class="mw-page-title-main">MDC1</span> Protein-coding gene in the species Homo sapiens

Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1).

<span class="mw-page-title-main">RNF8</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair.

<span class="mw-page-title-main">Homology directed repair</span>

Homology-directed repair (HDR) is a mechanism in cells to repair double-strand DNA lesions. The most common form of HDR is homologous recombination. The HDR mechanism can only be used by the cell when there is a homologous piece of DNA present in the nucleus, mostly in G2 and S phase of the cell cycle. Other examples of homology-directed repair include single-strand annealing and breakage-induced replication. When the homologous DNA is absent, another process called non-homologous end joining (NHEJ) takes place instead.

<span class="mw-page-title-main">MCM8</span> Protein-coding gene in the species Homo sapiens

DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8 gene.

The MRX complex is a heterotrimeric protein complex consisting of Mre11, Rad50, and Xrs2. It is a budding yeast homolog of the mammalian Mre11-Rad50-Nbs1 (MRN) DNA damage repair complex.

Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ is the use of microhomologous sequences during the alignment of broken ends before joining, thereby resulting in deletions flanking the original break. MMEJ is frequently associated with chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements.

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.

<span class="mw-page-title-main">DNA end resection</span> Biochemical process

DNA end resection, also called 5′–3′ degradation, is a biochemical process where the blunt end of a section of double-stranded DNA (dsDNA) is modified by cutting away some nucleotides from the 5' end to produce a 3' single-stranded sequence. The presence of a section of single-stranded DNA (ssDNA) allows the broken end of the DNA to line up accurately with a matching sequence, so that it can be accurately repaired.

<span class="mw-page-title-main">Double-strand break repair model</span>

A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).

References

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