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Cells Jul 2020DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of... (Review)
Review
DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.
Topics: Animals; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Damage; DNA Repair; Gene Editing; Humans
PubMed: 32664329
DOI: 10.3390/cells9071665 -
Genes & Development Mar 2022DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to... (Review)
Review
DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.
Topics: DNA Damage; DNA Repair; Genomic Instability; Humans; Immunotherapy; Neoplasms
PubMed: 35318271
DOI: 10.1101/gad.349431.122 -
ELife Jan 2021Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality.... (Review)
Review
Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.
Topics: Aging; Animals; DNA Damage; Humans; Inflammation; Proteostasis
PubMed: 33512317
DOI: 10.7554/eLife.62852 -
Nature Reviews. Clinical Oncology Jul 2020For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis.... (Review)
Review
For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.
Topics: Apoptosis; DNA Damage; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 32203277
DOI: 10.1038/s41571-020-0341-y -
Mechanisms of Ageing and Development Sep 2021The skin is comprised of different cell types with different proliferative capacities. Skin aging occurs with chronological age and upon exposure to extrinsic factors... (Review)
Review
The skin is comprised of different cell types with different proliferative capacities. Skin aging occurs with chronological age and upon exposure to extrinsic factors such as photodamage. During aging, senescent cells accumulate in different compartments of the human skin, leading to impaired skin physiology. Diverse skin cell types may respond differently to senescence-inducing stimuli and it is not clear how this results in aging-associated skin phenotypes and pathologies. This review aims to examine and provide an overview of current evidence of cellular senescence in the skin. We will focus on cellular characteristics and behaviour of different skin cell types undergoing senescence in the epidermis and dermis, with a particular focus on the complex interplay between mitochondrial dysfunction, autophagy and DNA damage pathways. We will also examine how the dermis and epidermis cope with the accumulation of DNA damage during aging.
Topics: Aging; Autophagy; Cellular Senescence; DNA Damage; Humans; Mitochondria; Skin; Skin Aging
PubMed: 34166688
DOI: 10.1016/j.mad.2021.111525 -
Molecular Cell Oct 2022The DNA-PKcs kinase mediates the repair of DNA double-strand breaks via classical non-homologous end joining (NHEJ). DNA-PKcs is also recruited to active replication...
The DNA-PKcs kinase mediates the repair of DNA double-strand breaks via classical non-homologous end joining (NHEJ). DNA-PKcs is also recruited to active replication forks, although a role for DNA-PKcs in the control of fork dynamics is unclear. Here, we identify a crucial role for DNA-PKcs in promoting fork reversal, a process that stabilizes stressed replication forks and protects genome integrity. DNA-PKcs promotes fork reversal and slowing in response to several replication stress-inducing agents in a manner independent of its role in NHEJ. Cells lacking DNA-PKcs activity show increased DNA damage during S-phase and cellular sensitivity to replication stress. Notably, prevention of fork slowing and reversal via DNA-PKcs inhibition efficiently restores chemotherapy sensitivity in BRCA2-deficient mammary tumors with acquired PARPi resistance. Together, our data uncover a new key regulator of fork reversal and show how DNA-PKcs signaling can be manipulated to alter fork dynamics and drug resistance in cancer.
Topics: Drug Resistance, Neoplasm; DNA Breaks, Double-Stranded; DNA Damage; DNA End-Joining Repair; DNA; DNA Replication; DNA Repair
PubMed: 36130596
DOI: 10.1016/j.molcel.2022.08.028 -
International Journal of Molecular... Aug 2021The active metabolites of vitamin D (D) and lumisterol (L) exert a variety of antiaging and photoprotective effects on the skin. These are achieved through... (Review)
Review
The active metabolites of vitamin D (D) and lumisterol (L) exert a variety of antiaging and photoprotective effects on the skin. These are achieved through immunomodulation and include anti-inflammatory actions, regulation of keratinocytes proliferation, and differentiation programs to build the epidermal barrier necessary for maintaining skin homeostasis. In addition, they induce antioxidative responses, inhibit DNA damage and induce DNA repair mechanisms to attenuate premature skin aging and cancerogenesis. The mechanism of action would involve interaction with multiple nuclear receptors including VDR, AhR, LXR, reverse agonism on RORα and -γ, and nongenomic actions through 1,25D-MARRS receptor and interaction with the nongenomic binding site of the VDR. Therefore, active forms of vitamin D including its canonical (1,25(OH)D) and noncanonical (CYP11A1-intitated) D derivatives as well as L derivatives are promising agents for the prevention, attenuation, or treatment of premature skin aging. They could be administrated orally and/or topically. Other forms of parenteral application of vitamin D precursor should be considered to avoid its predominant metabolism to 25(OH)D that is not recognized by CYP11A1 enzyme. The efficacy of topically applied vitamin D and L derivatives needs further clinical evaluation in future trials.
Topics: Animals; Antioxidants; DNA Damage; Humans; Skin; Skin Aging; Vitamin D
PubMed: 34445803
DOI: 10.3390/ijms22169097 -
Nature Reviews. Molecular Cell Biology Jun 2022Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and... (Review)
Review
Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA-protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.
Topics: DNA Damage; DNA Replication; Genomic Instability; Humans; Mitochondria; Neoplasms
PubMed: 35228717
DOI: 10.1038/s41580-022-00452-3 -
PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends.Cell Feb 2024DNA double-strand breaks (DSBs) are repaired at DSB sites. How DSB sites assemble and how broken DNA is prevented from separating is not understood. Here we uncover that...
DNA double-strand breaks (DSBs) are repaired at DSB sites. How DSB sites assemble and how broken DNA is prevented from separating is not understood. Here we uncover that the synapsis of broken DNA is mediated by the DSB sensor protein poly(ADP-ribose) (PAR) polymerase 1 (PARP1). Using bottom-up biochemistry, we reconstitute functional DSB sites and show that DSB sites form through co-condensation of PARP1 multimers with DNA. The co-condensates exert mechanical forces to keep DNA ends together and become enzymatically active for PAR synthesis. PARylation promotes release of PARP1 from DNA ends and the recruitment of effectors, such as Fused in Sarcoma, which stabilizes broken DNA ends against separation, revealing a finely orchestrated order of events that primes broken DNA for repair. We provide a comprehensive model for the hierarchical assembly of DSB condensates to explain DNA end synapsis and the recruitment of effector proteins for DNA damage repair.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Poly (ADP-Ribose) Polymerase-1; Humans
PubMed: 38320550
DOI: 10.1016/j.cell.2024.01.015 -
Advanced Science (Weinheim,... Feb 2023Triple-negative breast cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. Because of limited therapeutics against TNBC,...
Triple-negative breast cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. Because of limited therapeutics against TNBC, irradiation (IR) therapy is still a common treatment option for patients with lymph nodes or brain metastasis. Thus, it is urgent to develop strategies to enhance the sensitivity of TNBC tumors to low-dose IR. Here, the authors report that E3 ubiquitin ligase Ring finger protein 126 (RNF126) is important for IR-induced ATR-CHK1 pathway activation to enhance DNA damage repair (DDR). Mechanistically, RNF126 physically associates with the MRE11-RAD50-NBS1 (MRN) complex and ubiquitinates MRE11 at K339 and K480 to increase its DNA exonuclease activity, subsequent RPA binding, and ATR phosphorylation, promoting sustained DDR in a homologous recombination repair-prone manner. Accordingly, depletion of RNF126 leads to increased genomic instability and radiation sensitivity in both TNBC cells and mice. Furthermore, it is found that RNF126 expression is induced by IR activating the HER2-AKT-NF-κB pathway and targeting RNF126 expression with dihydroartemisinin significantly improves the sensitivity of TNBC tumors in the brain to IR treatment in vivo. Together, these results reveal that RNF126-mediated MRE11 ubiquitination is a critical regulator of the DDR, which provides a promising target for improving the sensitivity of TNBC to radiotherapy.
Topics: Animals; Humans; Mice; DNA Damage; DNA Repair; MRE11 Homologue Protein; Triple Negative Breast Neoplasms; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 36563124
DOI: 10.1002/advs.202203884