How the DNA Damage Response Modifies Transcription Regulators

Dear Colleagues,

This Special Issue aims to further our understanding of how the DNA Damage Response (DDR) utilizes Transcription Regulators (trx) to ensure genome stability. According to our current understanding, the DDR acts on three levels to achieve its goal: Firstly, it employs epigenetic chromatin modifiers that modulate the chromatin landscape. Secondly, the DDR orchestrates a network of signaling kinases that directly phosphorylate trx factors. Finally, it makes use of post-trx mechanisms like the efficiency of mRNA translation and conditional mRNA degradation.

1. Direct Regulation of Trx Factors

Master kinases such as ATM and ATR sense DNA lesions like double-strand breaks or stalled replication forks and directly modify trx factors to alter their activity and abundance. Famous examples are:

• p53 Activation: ATM and ATR phosphorylate p53 at S15 and its negative regulator MDM2, leading to the stabilization of p53 and its nuclear accumulation. This triggers the trx of genes for cell cycle arrest (p21) and apoptosis (BAX and PUMA).
• NF-κB and AP-1: DDR signaling activates the NF-κB pathway through the ATM/NEMO axis and stimulates AP-1 (via MAPK signaling), promoting the expression of anti-apoptotic and DNA repair genes.
• E2F Family Modulation: DDR kinases regulate E2F trx factors to manage the G1/S transition. For example, ATM-mediated phosphorylation of E2F1 can induce pro-apoptotic pathways, while the regulation of E2F6 or E2F7 can act as a check to prevent inappropriate repair or cell cycle entry.

2. Epigenetic and Chromatin-Based Regulation

DDR factors actively remodel chromatin to silence trx near damage sites (in cis) or globally (in trans) to prevent collisions between trx and DNA repair machinery. Examples include:

• Trx Silencing: ATM recruits Polycomb Repressive Complex 1 (PRC1) and the NuRD complex to damage sites, where they ubiquitinate H2AK119 and deacetylate histones to compact chromatin and evict RNA Polymerase II.
• Histone Modifications: PARP1 PARylates itself and other proteins at break sites, recruiting chromatin remodelers like ALC1 and histone demethylases like KDM5A to transiently suppress trx while facilitating repair.
• Regulator Switching: Dephosphorylation of H2AX-pY142 by ATM-dependent phosphatases EYA1/3 disrupts its interaction with RNA Pol II, effectively shutting down ongoing trx at active loci.

3. Post-Transcriptional Regulation

The DDR further regulates trx by managing the half-life and translation efficiency of already existing mRNAs through RNA-binding proteins (RBPs) and microRNAs. For example:

• mRNA Stabilization: Kinases like MK2 (activated by p38/ATM) phosphorylate RBPs such as hnRNP A0 and HuR. This enhances their binding to specific transcripts like Gadd45α or p21, stabilizing the mRNA to ensure a sustained response even while global de novo trx is inhibited.
• MicroRNA Induction: p53 and other DDR factors induce specific microRNAs like the miR-34 family that repress target mRNAs involved in cell cycle progression (like C-MYC and CDC25A), thereby enforcing arrest until repair is complete.

We encourage the submission of original research articles and contemporary review articles that extend the current understanding of the link between the DDR and Trx.

We look forward to receiving your contributions for this Cells Special Issue.

Dr. Norbert Lehming
Guest Editor

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