To safeguard genome integrity, cells channel DNA double-strand breaks (DSBs) to repair pathway of either DNA end-joining or homology-directed repair. The MRE11-RAD50-NBS1 (MRN) complex functions in both pathways, teaming up with the right co-factors to ensure the correct repair of DSBs. The MRN complex is well known as a nuclease capable of resecting DNA in both endonucleolytic and exonucleolytic manners. At occupied DSB ends, DNA end resection is initiated by the “endonucleolytic cleavage followed by exonucleolytic digestion” action of MRN, with endonucleolytic cleavage specifically requiring phosphorylated CtIP being present. Previous studies by us and the other groups in the field help to uncover the mechanistic details of the MRN-CtIP nuclease ensemble functioning in DNA end resection and homologous recombination (HR), although many unclear parts still exist. Besides DSB repair, replication fork processing, R-loop, and transcription–replication conflict (TRC) resolution also have been suggested by accumulating studies to be relevant to MRN and CtIP. In this review, we will summarize current knowledge about the MRN-CtIP nuclease ensemble, its functions in DNA processing in various contexts that could generate genome instability, how this complex is regulated and its relevance to diseases like cancers.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) forms DNA-PK holoenzyme with Ku70/Ku80 heterodimer, which initiates the (non-homologous end-joining) NHEJ repair upon double-strand breaks (DSBs). Besides function in NHEJ, DNA-PKcs also plays multiple roles in other biological processes including transcription, telomere maintenance, autophagy, cell cycle checkpoint, and lymphocyte development. Dysregulation of DNA-PKcs associates with various diseases such as genome instability and cancer, immunological deficiency, and neurological disorders. DNA-PKcs function is strictly controlled by post-translational modifications, especially phosphorylation. DNA-PKcs phosphorylation affects either the end-processing or the end-joining in DSB repair or Variable (V) Diversity (D) and Joining (J)/Class switch recombination in lymphocytes development. With increasing evidence of proteomic advances in DNA-PKcs study, other PTMs have been added including ubiquitination, neddylation, acetylation, and PARylation. Different DNA-PKcs PTMs may be involved different pathophysiological activities. Moreover, complexed crosstalk between DNA-PKcs phosphorylation and other PTMs will further aid the understanding of DNA-PKcs biology.
TOPBP1 (Topoisomerase IIβ-binding protein 1) mediates protein–protein interaction and DNA damage response (DDR) activation in DNA damage sensing and signaling to maintain genome integrity. However, the cancer-associated mutations of TOPBP1 have not been well studied. Here, 369 variants of TOPBP1 across 31 types of human cancer from three databases: The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Catalogue of Somatic Mutations in Cancer (COSMIC), were analyzed. We found that six truncation mutations of TOPBP1 impaired its ability to repair DNA lesions and activate damage checkpoint, and ten missense mutations impaired the recruitment of TOPBP1 to DNA damage sites. Therefore, DNA damage repair capacity and cell cycle arrest in G2/M phase were disrupted. The structural modeling also confirms that missense mutations of TOPBP1 change the local spatial structure, which may further abolish the function of TOPBP1 in DDR. Taken together, our study reveals the functional defects of cancer-associated TOPBP1 mutations in DDR and may provide new therapy targets for cancer treatment.
Centrosomes are the major microtubule-organizing center (MTOC), which are important cytoplasmic organelles regulating cell cycle, cell morphology, genomic stability, etc. The role of centrosomes on genomic stability has been reported in different conditions. Centrosomal proteins such as centrin2, pericentrin (PCNT), CEP164 have been reported to facilitate DNA damage repair. Various DNA damage response (DDR) proteins locate on centrosomes or microtubules, such as ATM, ATR, DNA-PKcs, 53BP1, etc. Meanwhile, microtubules serve as the “highway” for the transportation of DNA damage proteins into the nucleus. Microtubules have also been discovered to regulate the DNA double strands breaks (DSBs) mobility in DSBs repair. In this review, we first summarize the association between centrosome, microtubules, and DDR. Further, we discuss the new progression on how cells coordinate DDR with microtubule dynamics to facilitate DSBs repair.
DNA, which carries information to build the entire human body, is constantly challenged by a variety of endogenous and environmental agents, ultimately leading to mutations and genomic instability, triggering a wide range of cellular responses and causing diverse human diseases. Cells have evolved a variety of DNA repair mechanisms to respond to DNA damage. Recent findings have linked DNA damage in the brain with many neurological diseases. In this review, we discuss how DNA damage in the brain correlates with Alzheimer’s disease and how the absence of repair mechanisms accelerates age-related Alzheimer’s disease progression. We also review the potential sources of DNA damage, which may be closely associated with cognitive decline in Alzheimer’s disease.