The role of NBS1 in the modulation of PIKK family proteins ATM and ATR in the cellular response to DNA damage

Abstract

Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases have been considered the primary activators of the cellular response to DNA damage. They belong to the protein kinase family, phosphoinositide 3-kinase-related kinase (PIKKs). In human beings, deficiency of these kinases leads to hereditary diseases, namely ataxia telangiectasia (AT) with ATM deficiency and ATR-Seckel with ATR deficiency. NBS1, a component of MRE11/RAD50/ NBS1 (MRN) complex, is another important player in DNA damage response (DDR). Mutations of NBS1 are responsible for Nijmegen breakage syndrome (NBS), a human hereditary disease with the characteristics that almost encompassed those of AT and ATR-Seckel. NBS1 has been conventionally thought to be a downstream substrate of ATM and ATR in DDR; however, recent studies suggest that NBS1/MRN functions upstream of both ATM and ATR by recruiting them to the proximity of DNA damage sites and activating their functions. In this mini-review, we would emphasize the requirement of NBS1 as an upstream mediator for the modulation of PIKK family proteins ATM and ATR. Keywords DNA damage response; NBS1; PIKKThe DNA in our cells is under constant challenge by damaging agents, which include external factors, such as ultraviolet light (UV), ionizing radiation (IR), and other natural or man-made mutagens. It is also subject to damage by internal factors, including the byproducts of oxidative metabolism and stalled replication forks. Cells maintain a sophisticated system to deal with these damages. After the detection of the existence of DNA damage by sensor molecules, the DNA damage signals will be amplified and diversified, by signal transducers, to a set of downstream effectors. The downstream effectors trigger cellular events such as DNA repair, cell cycle checkpoint, telomere stability maintaenance, transcription control, and apoptosis. Together, the process mentioned above, NBS1 is another key player in DDR, as a component of MRE11/RAD50/NBS1 (MRN) complex. NBS1 itself does not have DNA binding/processing and kinase activity that are usually required for DNA damage repair. The FHA/BRCT domain in the N-terminus of NBS1, however, has been shown to bind directly to phosphorylated histone H2AX (γH2AX). The binding of NBS1 to γH2AX recruits other members of MRN (MRE11 and RAD50) to the proximity of DNA damage sites [7]. Certainly, other unknown γH2AX-independent mechanisms may also contribute to the binding of MRN to DNA ends [8]. MRE11 possesses several biochemical properties, such as 3′-5′ double-strand DNA exonuclease, single-strand DNA endonuclease, and DNA unwinding activity that are required for DNA DSB repair. RAD50 is a member of the structure maintenance of chromosome (SMC) protein family. RAD50 has two ATPase motifs at its N-and C-terminal ends and forms an anti-parallel homodimer with a flexible hinge region that may adopt a `Vlike' conformation. The `V-like' structure could serve as a bridge to hold together the broken ends of DSB for avoiding them to fl...

Cell Cycle- and Proteasome-Dependent Formation of Etoposide-Induced Replication Protein A (RPA) or Mre11/Rad50/Nbs1 (MRN) Complex Repair Foci

“…The MRN complex has been proposed to be a sensor of DNA damage, 29,30 and is known to be necessary for full activation of the ATM and ATR kinases [31][32][33][34][35][36][37][38][39][40] (reviewed in ref. 41). Null mutations in any component of the MRN complex lead to embryonic lethality, [42][43][44] while hypomorphic mutations in Mre11 lead to the clinical syndrome Ataxia telangiectasia-like disorder (ATLD) 45 and hypomorphic mutations in Nbs1 lead to Nijmegen breakage syndrome (NBS).…”

Sp1 Facilitates DNA Double-Strand Break Repair through a Nontranscriptional Mechanism

“…Inactive ATM forms homodimers and is activated by intermolecular phosphorylation at serine 1981 and dissociation into monomers (4). The complex of Mre11, Rad50, and Nbs1 (MRN) binds to DSBs, facilitates the recruitment of ATM through direct interaction with the C terminus of Nbs1 (18,50,93), and enhances phosphorylation of ATM substrates (45,48,49,87). The MRN complex enhances ATM activation and thereby affects phosphorylation of several ATM substrates, including Chk2 and p53 (11,24,25,83).…”

ATR Pathway Is the Primary Pathway for Activating G2/M Checkpoint Induction After Re-replication

“…The Rad17-RFC and 9-1-1 complexes are involved in ATR/ Chk1 pathway, whereas Mre11-Rad50-Nbs1 (MRN) complex is implicated to play an important role in ATM/Chk2 pathway (16,25). MRN complex was suggested to work in both DNA damage checkpoint and repair pathways (26,27).…”