LIM Protein Ajuba Participates in the Repression of the ATR-Mediated DNA Damage Response

Abstract

LIM proteins constitute a superfamily characterized by the presence of a LIM domain, known to be involved in protein–protein interactions. Our previous work has implicated members of the Zyxin family of LIM proteins, namely TRIP6 and LPP, in the repression of the DNA damage response (DDR) at telomeres. Here, we describe a role for Ajuba, a closely related LIM molecule, in repressing the ATR-mediated DDR. We found that depletion of Ajuba led to apparent delays in the cell cycle, accompanied with increased Rb phosphorylation, Chk1 phosphorylation, induction of p53, and cell death. Ajuba could be found in a complex with replication protein A (RPA), and its depletion led to RPA phosphorylation, known to be an early event in ATR activation. We propose that Ajuba protects against unscheduled ATR signaling by preventing inappropriate RPA phosphorylation.

(-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization

“…IMR90 cells did not show a significant decrease in Rb phosphorylation at Ser 608, probably reflecting cell cycle arrest outside of G1. 17 These data suggest that OC treatment does not induce cell death in non-cancerous cells but rather reversibly induces cell cycle arrest via suppression of Rb phosphorylation, which serves to protect healthy cells against the adverse effects of OC.…”

LIM Protein Ajuba associates with the RPA complex through direct cell cycle-dependent interaction with the RPA70 subunit

“…The Zyxin family is characterized by the presence of three C-terminal LIM domains 16 . We have shown that Ajuba acts as a negative regulator of ATR in unperturbed cells 14 . Notably, upon depletion of the protein, cells experience S phase delay along with strong activation of Chk1, a known ATR substrate, and undergo apoptosis.…”

“…The complex has a structural role given its ability to bind single stranded DNA, thereby preventing secondary structures incompatible with replication or repair, and a signaling role related to the assembly of the ATR activation complex on RPA70N. We have previously implicated the LIM (LIN-1, ISL-1, MEC-1) domain protein Ajuba as a new player in the ATR pathway 14 . The LIM superfamily of proteins, constituted by 60 members in the human proteome, is subdivided into seventeen families, all with predicted LIM domains in various arrangements 15 , 16 .…”

Comprehensive genomic characterization of head and neck squamous cell carcinomas

“…AJUBA is a centrosomal protein that regulates cell division, vertebrate ciliogenesis, and left-right axis determination 24 . Additionally, AJUBA is subject to EGFR-RAS-MAPK-dependent phosphorylation and implicated in Hippo growth and regeneration pathways conserved from Drosophila to mammals 25 , 26 , in ATR-mediated DNA damage response, 27 and tumor invasion and migration 28 .…”