DNA damage repair (DDR) proteins are well recognized as guardians of the genome that are frequently lost during malignant transformation of normal cells across cancer types. To date, their tumor suppressor functions have been generally regarded as a consequence of their roles in maintaining genomic stability: more genomic instability increases the risk of oncogenic transformation events. However, recent discoveries centering around DNA mismatch repair (MMR) proteins suggest a broader impact of the loss of DDR proteins on cellular processes beyond genomic instability. Here, we explore the clinical implications of nonrepair roles for DDR proteins, using the growing evidence supporting roles for DNA MMR proteins in cell cycle and apoptosis regulation, metabolic function, the cellular secretome, and immunomodulation.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.trecan.2024.10.001 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Interaction of DDB1 with NBS1 in a DNA Damage Checkpoint Pathway.
Int J Mol Sci
December 2024
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Republic of Korea.
Various DNA damage checkpoint control mechanisms in eukaryotic cells help maintain genomic integrity. Among these, NBS1, a key component of the MRE11-RAD50-NBS1 (MRN) complex, is an essential protein involved in the DNA damage response (DDR). In this study, we discovered that DNA damage-binding protein 1 (DDB1) interacts with NBS1.
View Article and Find Full Text PDFCombined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer.
Cancers (Basel)
November 2024
Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy.
Background: Oncogene-driven NSCLC is usually treated with targeted therapies using tyrosine kinase inhibitors (TKIs) to inhibit oncogene downstream signaling pathways, affecting tumor survival and proliferation. EGFR- and KRAS-mutant NSCLCs are the most represented subtypes, and they are treated in clinical practice with oncogene-targeting drugs in the first and second line, respectively. Unfortunately, the development of oncogene-independent resistant clones limits TKI efficacy.
View Article and Find Full Text PDFA goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions.
Front Mol Biosci
November 2024
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
While many researchers can design knockdown and knockout methodologies to remove a gene product, this is mainly untrue for new chemical inhibitor designs that empower multifunctional DNA Damage Response (DDR) networks. Here, we present a robust Goldilocks (GL) computational discovery protocol to efficiently innovate inhibitor tools and preclinical drug candidates for cellular and structural biologists without requiring extensive virtual screen (VS) and chemical synthesis expertise. By computationally targeting DDR replication and repair proteins, we exemplify the identification of DDR target sites and compounds to probe cancer biology.
View Article and Find Full Text PDFMapping functional elements of the DNA damage response through base editor screens.
Cell Rep
December 2024
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China. Electronic address:
Maintaining genomic stability is vital for cellular equilibrium. In this study, we combined CRISPR-mediated base editing with pooled screening technologies to identify numerous mutations in lysine residues and protein-coding genes. The loss of these lysine residues and genes resulted in either sensitivity or resistance to DNA-damaging agents.
View Article and Find Full Text PDFSeparable roles of the DNA damage response kinase Mec1ATR and its activator Rad24RAD17 during meiotic recombination.
PLoS Genet
December 2024
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, United Kingdom.
During meiosis, programmed DNA double-strand breaks (DSBs) are formed by the topoisomerase-like enzyme, Spo11, activating the DNA damage response (DDR) kinase Mec1ATR via the checkpoint clamp loader, Rad24RAD17. At single loci, loss of Mec1 and Rad24 activity alters DSB formation and recombination outcome, but their genome-wide roles have not been examined in detail. Here, we utilise two strategies-deletion of the mismatch repair protein, Msh2, and control of meiotic prophase length via regulation of the Ndt80 transcription factor-to help characterise the roles Mec1 and Rad24 play in meiotic recombination by enabling genome-wide mapping of meiotic progeny.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!