ATR Signaling and DNA Damage Response Mechanisms

The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of the cellular response to replication stress and DNA damage. ATR detects stretches of single-stranded DNA coated by replication protein A (RPA) that arise at stalled replication forks or resected DNA double-strand breaks. Upon recruitment by its partner ATRIP, ATR phosphorylates a network of substrates, notably the checkpoint kinase CHK1, to delay cell-cycle progression, stabilise replication forks and promote DNA repair pathways such as homologous recombination. ATR signalling integrates with scaffold proteins including TopBP1 and the 9-1-1 clamp to fine-tune checkpoint activation. Dysregulation of ATR or its cofactors compromises genome stability, drives mutagenesis and contributes to oncogenesis. Conversely, targeted modulation of ATR signalling shows promise in sensitising tumour cells to genotoxic therapies. Advances in structural biology, biochemical reconstitution and live-cell imaging continue to reveal the temporal and spatial dynamics of ATR activation and its cooperation with the broader DNA damage response network.

Research from Nature Portfolio

A recent study has identified ZNF827 as a novel single-stranded DNA-binding protein that directly engages RPA-coated DNA intermediates. ZNF827 is recruited to stalled forks and damage sites, where it promotes ATR activation and enhances homologous recombination-mediated repair. Depletion of ZNF827 impairs replication initiation and sensitises cancer cells to topoisomerase inhibitors, revealing a potential therapeutic vulnerability within the ATR-CHK1 axis. Another foundational contribution has elucidated how nucleolar integrity is maintained upon breaks in ribosomal DNA. It demonstrates that the nucleolar phosphoprotein Treacle is phosphorylated in response to damage, creating binding sites for TopBP1. Recruitment of TopBP1 to damaged rDNA depends on cooperative ATM and ATR activity, leading to inhibition of ribosomal RNA synthesis and nucleolar segregation. This work highlights an unexpected role for ATR in regulating nucleolar architecture and transcriptional repression following rDNA damage.

ATR Signaling and DNA Damage Response Mechanisms publication trend

The graph below shows the total number of articles in atr signaling and dna damage response mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

ATR kinase: A phosphatidylinositol 3-kinase-related kinase that detects RPA-coated single-stranded DNA and orchestrates cell-cycle checkpoints and repair.

Replication stress: Perturbations in DNA replication resulting from obstacles to fork progression, leading to ssDNA exposure and checkpoint activation.

Single-stranded DNA (ssDNA): DNA that results from unwound or resected duplexes, serving as a platform for RPA binding and checkpoint signalling.

RPA (replication protein A): A heterotrimeric complex that binds ssDNA, stabilises it and recruits ATR-ATRIP for checkpoint initiation.

CHK1: A serine/threonine checkpoint kinase phosphorylated by ATR to enforce cell-cycle arrest and promote DNA repair.

Homologous recombination: An error-free DNA repair pathway that uses a sister chromatid template to restore genetic information at double-strand breaks.

TopBP1: A scaffold protein containing multiple BRCT domains that activates ATR and couples checkpoint signalling with DNA repair.

References

1. ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway. Nature Communications (2024).
2. Pre‐rRNA Facilitates TopBP1‐Mediated DNA Double‐Strand Break Response. Advanced Science (2023).
3. Multi-step control of homologous recombination via Mec1/ATR suppresses chromosomal rearrangements. The EMBO Journal (2024).
4. Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation. Nature Communications (2020).