Sincronizadores absolutos

Double-strand break repair protein (meiotic recombination protein 11), or MRE11, is encoded on human chromosome 11 (11q21), as is ATM. Similar to ATM, MRE11 is highly-conserved amongst present day species, carrying out analogous DDR functions in yeasts, fish, plants and diverse birds, not to mention mammals (Zdobnov et al., 2017). An orthologue of MRE11 has recently been documented in the archaeon Sulfolobusacidocaldarius, which lives by volcanic vents at 82oC and pH 2-3. When this organism is subjected to experimental radiation, Mre11 participates in DSB repair along with RAD50 (Quaiser et al., 2008); and suggests that this gene evolved from prokaryotic lineages.

In humans, MRE11 has a molecular weight between 70-90 kDa, with the predominant isoform consisting of 708 amino acids, making it less than a third the size of ATM, discussed previously. The N-terminus of the protein encodes the di-manganese-dependent phosphoesterase domain, whilst the C-terminus possesses two unique DNA-binding domains (Lamarche et al., 2010). Compared to many proteins, MRE11 has a relatively simple structure, perhaps a key feature allowing it to participate in diverse biochemical processes. As has been discussed for ATM, conformational changes are key to the protein’s function; that is considered ancient and pleiotropic proteins malleable and applicable to many tasks. For example, structural data has recently revealed that a RAD50-ATP-driven conformation switch in MRE11 controls the exonuclease function of the latter (Hopfner et al., 2001). MRE11 is also known to be controlled by a number of post-translational mechanisms to influence its localisation, function and longevity. For example, in order for ATM to function in DNA damage repair, it has to be arginine methylated by PRMT1 (Boisvert et al., 2005).

The most notable functions of MRE11 are described in the context of the previously introduced MRN complex, which it forms along with RAD50 and NBS1. As part of this macromolecular assembly, MRE11 participates in the repair of DSBs using a combination of homology directed repair, and classical and alternative non-homologous end-joining. Overall, the predominant function of the MRN complex is to repair DSBs via homology directed repair between sister chromatids (Bressan et al., 1999). Furthermore, in addition to MRE11’s DNA-binding roles, described below, the protein also has exo- and endo-nuclease activity against both single- and double-stranded DNA. Importantly, although MRE11 is a potent sequence modifier, it does not possess the 5’-3’ exonuclease activity required to generate 3’ single-strand overhangs required for homologous recombination (Lamarche et al., 2010). Therefore, auxiliary factors are likely recruited to the MRN complex to assist with homologous recombination, and to date, several 5’-3’ exonucleases, such as XRN2, have been identified in man (West et al., 2004). In-keeping with its best described functions, MRE11 has a mostly nuclear localisation, endowing it with close approximation to the genomic material it aims to repair. However, it is also able to translocate to the cytoplasm, as required, to carry out other functions. A good example is illustrated by the instructive role of MRE11 in driving type I interferon signalling and STING trafficking in response to detecting pathogen dsDNA in the cytoplasm (Kondo et al., 2013); which also highlights an important unrelated role of the protein. Although it is useful to consider the sub-cellular localisation of proteins when considering their potential functions, much remains to be determined by using more modern microscopy approaches that allow spatial and temporal dynamics to be interrogated in response to different stimuli (Lanzano et al., 2015).

The nuclear MRN complex as a whole, has a large central globular domain, where MRE11 and NBS1 associate with RAD50 via the latter’s extended coil-coil and Walker A and B domains (Stracker and Petrini, 2011). It is also the globular domain that mediates nucleic acid binding, usually as part of a higher-order assembly of multiple entities (De Jager et al., 2004), and is dependent on MRE11 and RAD50, but not (according to the majority of studies) NBS1 (Schiller et al., 2014). Furthermore, it is known that dimerization of MRE11 is required for DNA binding, with dimerization being mediated by the N-terminal region of the protein; and persists in recombinant MRE11 in vitro(Williams et al., 2008). Unfortunately, the crystal structure of the entire assembled globular domain is yet to be determined, which would help address these points relating to function further; although again, advances in cryo-EM may overcome this limitation in the near future. With respect to MRE11, however, crystallographic data has revealed that the protein contacts DNA via 17 conserved residues distributed across DNA recognition loops, with the aforementioned residues forming minor-groove sugar- phosphate contacts (Stracker and Petrini, 2011). This dependency on sugar-phosphate contacts, and not nucleotide bases for DNA binding, allows MRE11 to bind a wide array of sequences, irrespective of the base pair sequence – a feature shared with ATM.

Given the ancient nature of the proteins discussed thus far, it is perhaps unsurprising that the DDR is a major function of MRE11. For example, in our species, and in quite remarkable

experiments, Schwartz and colleagues also found the MRN complex to also be a potent mediator of anti-viral immunity. In cells infected with parvoviruses, MRN complex dissolution led to the accumulation of MRE11, RAD50 and NBS1 on viral inverted terminal repeat regions (Schwartz et al., 2007), suggesting the complex is able to detect foreign nucleic acids as well as those of host origin. Work by Deng and colleagues has also shown multiple roles for MRE11 at the telomere end (Deng et al., 2009). In elegant work, the authors show that in the absence of TRF, MRE11 is able to remove 3’ telomeric overhangs, allowing for chromosomal fusions, and protects nascent strands from NHEJ. Essentially, MRE11 is involved in sensing telomere dysfunction and maintenance. This work came on the back of that of Zhong and colleagues, who showed that an absence of the MRN complex resulted in reduced telomere maintenance (Zhong et al., 2007). This study also showed, as have others, that a knock-down of MRE11, leads to a knock-down of the entire MRN complex, highlighting the central role of this DNA binder to one of the most studied biochemical complexes. Furthermore, in mice, expression of a hypomorphic Mre11 allele caused the premature elimination of oocytes harbouring DNA mutations, although oocyte attrition took much longer than in animals with a fully competent MRN complex (Inagaki et al., 2016). Thus, variants that alter the expression level or isoforms of MRE11 will need to be considered as putative pathological variants, and may lead to an increased oocyte and sperm mutation burden with disastrous consequences for the offspring. Before moving on to consider some of the specific associations between MRE11 and cancer, it is worth considering the distribution of this gene’s expression to learn more about its potential function and importance to cancer. According to the human tissue-wide compendium of mRNA expression, BioGPS, MRE11 mRNA is highly expressed in haematopoietic lineages, especially in cell lines derived from leukaemia and lymphoma patients (Wu et al., 2013). Highly proliferative B cells, or lymphoblasts, also express high amount of MRE11 mRNA, in keeping with its important role in genomic integrity maintenance in cells with a high turnover rate, such as those of the immune system. Adult human tissues at baseline expressed MRE11, but not significantly above mean levels; suggesting that MRE11 has more important functions in some lineages over others.

In agreement with such a distribution in mammals is data from the publicly available Immunological Genome Project (Heng and Painter, 2008) and Symatlas (Su et al., 2004). In these datasets, which analyse gene expression across the finely-dissected mouse, show the bone marrow, testis, and the embryo between days 6 and 10 of gestation, to have the highest expression levels. Interestingly, gastrointestinal inflammation, of diverse forms, is implicated with colorectal and rectal cancer development and progression (Kim and Chang, 2014; Tjalsma et al., 2012). If drivers of inflammation coincide with developmental processes typified by a high cell turnover rate, perhaps the foundations of cancer can be laid. Although much remains to be determined with regards to the aetiology of rectal cancer, immune cell dysregulation in specialised gastrointestinal microenvironments (such as Peyer’s patches) can drive oncogenesis arising in other lineages (Chapkin et al., 2007; Nascimbeni et al., 2005; Sipos and Muzes, 2011).

increasingly likely that individual clinical histories, and high-resolution analysis of our different organ systems (such as the microbiome) will be increasingly important in identifying causality – in line, of course, with our expanding knowledge of how genetics underpins and responds to environmental cues.