The MRE11, RAD50, and NBN genes encode for the nuclear MRN protein complex, which senses the DNA double strand breaks and initiates the DNA repair. The MRN complex also participates in the activation of ATM kinase, which coordinates DNA repair with the p53-dependent cell cycle checkpoint arrest. Carriers of homozygous germline pathogenic variants in the MRN complex genes or compound heterozygotes develop phenotypically distinct rare autosomal recessive syndromes characterized by chromosomal instability and neurological symptoms. Heterozygous germline alterations in the MRN complex genes have been associated with a poorly-specified predisposition to various cancer types. Somatic alterations in the MRN complex genes may represent valuable predictive and prognostic biomarkers in cancer patients. MRN complex genes have been targeted in several next-generation sequencing panels for cancer and neurological disorders, but interpretation of the identified alterations is challenging due to the complexity of MRN complex function in the DNA damage response. In this review, we outline the structural characteristics of the MRE11, RAD50 and NBN proteins, the assembly and functions of the MRN complex from the perspective of clinical interpretation of germline and somatic alterations in the MRE11, RAD50 and NBN genes.
- MeSH
- ATM protein genetika metabolismus MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- enzymy opravy DNA genetika metabolismus MeSH
- homologní protein MRE11 genetika metabolismus MeSH
- hydrolasy působící na anhydridy kyselin genetika metabolismus MeSH
- jaderné proteiny genetika metabolismus MeSH
- lidé MeSH
- nádorové supresorové proteiny * genetika MeSH
- oprava DNA genetika MeSH
- proteiny buněčného cyklu * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A growing body of evidence supports the notion that cancer resistance is driven by a small subset of cancer stem cells (CSC), responsible for tumor initiation, growth, and metastasis. Both CSC and chemoresistant cancer cells may share common qualities to activate a series of self-defense mechanisms against chemotherapeutic drugs. Here, we aimed to identify proteins in chemoresistant triple-negative breast cancer (TNBC) cells and corresponding CSC-like spheroid cells that may contribute to their resistance. We have identified several candidate proteins representing the subfamilies of DNA damage response (DDR) system, the ATP-binding cassette, and the 26S proteasome degradation machinery. We have also demonstrated that both cell types exhibit enhanced DDR when compared to corresponding parental counterparts, and identified RAD50 as one of the major contributors in the resistance phenotype. Finally, we have provided evidence that depleting or blocking RAD50 within the Mre11-Rad50-NBS1 (MRN) complex resensitizes CSC and chemoresistant TNBC cells to chemotherapeutic drugs.
- MeSH
- chemorezistence účinky léků genetika MeSH
- cisplatina aplikace a dávkování MeSH
- cyklofosfamid aplikace a dávkování MeSH
- DNA vazebné proteiny genetika MeSH
- doxorubicin aplikace a dávkování MeSH
- enzymy opravy DNA genetika MeSH
- homologní protein MRE11 genetika MeSH
- hydrolasy působící na anhydridy kyselin genetika MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- nádorové kmenové buňky účinky léků metabolismus MeSH
- poškození DNA účinky léků MeSH
- přežití po terapii bez příznaků nemoci MeSH
- proteiny buněčného cyklu genetika MeSH
- triple-negativní karcinom prsu farmakoterapie genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Nitrilases are highly conserved proteins with catabolic activity but much less understood functions in cell division and apoptosis. To elucidate the biological functions of Arabidopsis NITRILASE1, we characterized its molecular forms, cellular localization and involvement in cell proliferation and plant development. We performed biochemical and mass spectrometry analyses of NITRILASE1 complexes, electron microscopy of nitrilase polymers, imaging of developmental and cellular distribution, silencing and overexpression of nitrilases to study their functions. We found that NITRILASE1 has an intrinsic ability to form filaments. GFP-NITRILASE1 was abundant in proliferating cells, distributed in cytoplasm, in the perinuclear area and associated with microtubules. As cells exited proliferation and entered differentiation, GFP-NITRILASE1 became predominantly nuclear. Nitrilase silencing dose-dependently compromised plant growth, led to loss of tissue organization and sustained proliferation. Cytokinesis was frequently aborted, leading to enlarged polyploid cells. In reverse, independently transformed cell lines overexpressing GFP-NITRILASE1 showed slow growth and increased rate of programmed cell death. Altogether, our data suggest that NITRILASE1 homologues regulate the exit from cell cycle and entry into differentiation and simultaneously are required for cytokinesis. These functions are essential to maintain normal ploidy, genome stability and tissue organization.
- MeSH
- aminohydrolasy chemie genetika metabolismus ultrastruktura MeSH
- Arabidopsis cytologie genetika růst a vývoj MeSH
- buněčná diferenciace genetika MeSH
- buněčná smrt genetika MeSH
- buněčný cyklus genetika MeSH
- cytoplazma metabolismus MeSH
- cytoskelet genetika metabolismus MeSH
- hydrolasy působící na anhydridy kyselin genetika MeSH
- nádorové proteiny genetika MeSH
- nestabilita genomu * MeSH
- proliferace buněk MeSH
- regulace genové exprese u rostlin MeSH
- RNA interference MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH