Processing of DNA Double-Strand Breaks by the MRX Complex in a Chromatin Context

Abstract

DNA double-strand breaks (DSBs) are highly cytotoxic lesions that must be repaired to ensure genomic stability and avoid cell death. The cellular response to DSBs is initiated by the evolutionarily conserved Mre11-Rad50-Xrs2/NBS1 (MRX/MRN) complex that has structural and catalytic functions. Furthermore, it is responsible for DSB signaling through the activation of the checkpoint kinase Tel1/ATM. Here, we review functions and regulation of the MRX/MRN complex in DSB processing in a chromatin context, as well as its interplay with Tel1/ATM.

Metal Exchange in the Interprotein ZnII‐Binding Site of the Rad50 Hook Domain: Structural Insights into CdII‐Induced DNA‐Repair Inhibition

“…It is believed that the MR(N/X) complex is a flexible one with highly dynamic properties that enable it to adopt multiple conformational assemblies . Recent findings indicate that conformation‐altering signals can be generated both at Rad50’s ATPase globular and zinc hook domain apexes and transferred through an immensely long coiled‐coil segment that spans 500 Å . At this point, two conformational states of the MR(N/X) complex seem to play a major functional role: closed conformation that binds tightly to DNA substrates and open conformation that enables DNA processing and repair .…”

“…The increased difference in stability of the two complexes with rising peptide length favors the formation of the Zn(Hk) 2 species. The existence of an equimolar complex being in equilibrium with a dimer could be of high importance and suggests a possibility of readily exchangeable Rad50 molecules during cellular processes, which is believed to be the requirement for MRN native functions . Keeping in mind the toxic effect of Cd II on zinc finger domains of transcription factors and other zinc–sulfur proteins associated with DNA processing, we aimed to examine the impact of Cd II binding on the Rad50 protein using a well‐described model from P. furiosus , which would be the first intermolecular zinc‐binding site analyzed in terms of Cd II attack.…”

Immunometabolism in the development of rheumatoid arthritis

“…In the case of RA T cells, telomeric shortening was related to the loss of the DNA repair nuclease MRE11A (Figure ). MRE11A has 3' to 5' exonuclease and endonuclease activity and is required for DNA double‐strand break repair by homologous recombination . The nuclease partners with RAD50 and ATM to form the MRN complex and hypomorphic mutations of MRE11A cause ataxia‐telangiectasia‐like disorders.…”

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

“…When the stalled replication fork cannot be stabilized, fork then collapse into a double-strand break, which is the most lethal type of DNA damage [47]. In response to DSBs, the MRE11-RAD50-NBS1 (MRN) complex recruits ATM to damaged DNA sites and stimulates ATM kinase activity [48]. ATM then targets multiple substrates such as the downstream effector kinase CHK2 to induce cell cycle arrest, and to initiate DNA repair.…”

“…Thus, a 45 coherent understanding of how SCLC cells manipulate replication stress response (RSR) to control 46 DNA replication and to fix damaged DNA may facilitate the development of new therapeutic 47 strategies and circumvent drug resistance in the SCLC treatment. Recent advances in transcriptomics 48 and proteomics have identified a significantly elevated expression of a number of genes, which 49 encode vital proteins responsible for DNA damage response in SCLC including ATR, CHK1, WEE1, 50 and BRCA1 [17]. In recent years, a great amount of effort has been put on the discovery and 51 development of compounds that would exploit defects in DNA replication and DNA repair to treat 52…”