Dancing on Damaged Chromatin: Functions of ATM and the RAD50/MRE11/NBS1 Complex in Cellular Responses to DNA Damage

Abstract

In order to preserve and protect genetic information, eukaryotic cells have developed a signaling or communications network to help the cell respond to DNA damage, and ATM and NBS1 are key players in this network. ATM is a protein kinase which is activated immediately after a DNA double strand break (DSB) is formed, and the resulting signal cascade generated in response to cellular DSBs is regulated by post-translational protein modifications such as phosphorylation and acetylation. In addition, to ensure the efficient functioning of DNA repair and cell cycle checkpoints, the highly ordered structure of eukaryotic chromatin must be appropriately altered to permit access of repair-related factors to DNA. These alterations are termed chromatin remodeling, and are executed by a specific remodeling complex in conjunction with histone modifications. Current advances in the molecular analysis of DNA damage responses have shown that the auto-phosphorylation of ATM and the interaction between ATM and NBS1 are key steps for ATM activation, and that the association of ATM and NBS1 is involved in chromatin remodeling. Identification of novel factors which function in ubiquitination (RNF8, Ubc13, Rap80, etc.) has also enabled us to understand more details of the early stages in DNA repair pathways which respond to DSBs. In this review, the focus is on the role of ATM and the RAD50/MRE11/NBS1 complex in DSB response pathways, and their role in DSB repair and in the regulation of chromatin remodeling.

BMI1 Confers Radioresistance to Normal and Cancerous Neural Stem Cells through Recruitment of the DNA Damage Response Machinery

“…These sensor proteins will phosphorylate H2AX to generate ␥H2AX, which represents the first mark of DNA damage sensing. Following DNA damage recognition, mediator proteins such as BRCA1, MDC1, and 53BP1 amplify the signal, which is then transduced to downstream effectors (Lee and Paull, 2007;Iijima et al, 2008).…”

MRE11 Expression Is Predictive of Cause-Specific Survival following Radical Radiotherapy for Muscle-Invasive Bladder Cancer

“…Failure to repair such breaks results in tumor cell death. Immediately following cellular exposure to ionizing radiation, the damage is detected by the MRE11-RAD50-NBS1 (MRN) complex, resulting in rapid recruitment of signaling and repair proteins and alteration of chromatin structure, including histone modifications, to permit protein access to the DNA (5). MRE11/ RAD50 tethers broken DNA ends and NBS1 recruits ATM (6).…”

Defective ATM‐Kap‐1‐mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model

“…However, the underlying molecular mechanism remains largely unknown. Upon DNA damage, chromatin opens up for the loading and retention of repair proteins to DNA lesions (Iijima et al, 2008). To determine the chromatin accessibility, a micrococcal nuclease sensitivity assay was employed.…”