G-quadruplexes associated with R-loops promote CTCF binding

Molecular Cell, Год журнала: 2023, Номер 83(17), С. 3064 - 3079.e5

Опубликована: Авг. 7, 2023

Язык: Английский

---

The DNA Damage Response and Inflammation in Cancer

Cancer Discovery, Год журнала: 2023, Номер 13(7), С. 1521 - 1545

Опубликована: Апрель 7, 2023

Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting demise with unrepairable lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor progression resistance therapy. Indeed, signaling cancer has been consistently linked inhibition tumor-targeting immune responses. Here, we discuss complex interactions between inflammation context oncogenesis, progression, Accumulating preclinical clinical evidence indicates that intimately connected emission immunomodulatory signals malignant cells, part a program preserve organismal homeostasis. DDR-driven inflammation, however, have diametrically opposed effects on immunity. Understanding links may unlock novel immunotherapeutic paradigms treat cancer.

Язык: Английский

---

PARP1 associates with R-loops to promote their resolution and genome stability

Nucleic Acids Research, Год журнала: 2023, Номер 51(5), С. 2215 - 2237

Опубликована: Фев. 16, 2023

Abstract PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that triggered by DNA breaks and non-B structures to mediate their resolution. was also recently identified as component of the R-loop-associated protein-protein interaction network, suggesting potential role for in resolving this structure. R-loops are three-stranded nucleic acid consist RNA–DNA hybrid displaced non-template strand. involved crucial physiological processes but can be source genome instability if persistently unresolved. In study, we demonstrate binds vitro associates R-loop formation sites cells which activates its activity. Conversely, inhibition or genetic depletion causes an accumulation unresolved promotes genomic instability. Our study reveals novel sensor highlights suppressor

Язык: Английский

---

Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation

Leukemia, Год журнала: 2024, Номер 38(6), С. 1353 - 1364

Опубликована: Март 21, 2024

Abstract DEAD box helicase 41 (DDX41) mutations are the most prevalent predisposition to familial myelodysplastic syndrome (MDS). However, precise roles of these variants in pathogenesis MDS have yet be elucidated. Here, we discovered a novel mechanism by which DDX41 contributes R-loop-induced DNA damage responses (DDR) cooperation with m6A-METTL complex (MAC) and YTHDC1 using knockout (KO) knock-in (KI, R525H, Y259C) cell lines as well primary samples from patients. Compared wild type (WT), KO KI led increased levels m6A RNA methylated R-loop. Interestingly, found that regulates m6A/R-loop interacting MAC components. Further, promoted recruitment R-loops promoting binding between METTL3 YTHDC1, was dysregulated -deficient cells, contributing genomic instability. Collectively, demonstrated plays key role physiological control YTHDC1. These findings provide insights into how defects influence suggest potential therapeutic targets for treatment MDS.

Язык: Английский

---

Intertwining roles of R-loops and G-quadruplexes in DNA repair, transcription and genome organization

Nature Cell Biology, Год журнала: 2024, Номер 26(7), С. 1025 - 1036

Опубликована: Июнь 24, 2024

Язык: Английский

---

DEAD-Box RNA Helicases and Genome Stability

Genes, Год журнала: 2021, Номер 12(10), С. 1471 - 1471

Опубликована: Сен. 23, 2021

DEAD-box RNA helicases are important regulators of metabolism and have been implicated in the development cancer. Interestingly, these constitute a major recurring family RNA-binding proteins for protecting genome. Current studies provided insight into connection between genomic stability several helicase including DDX1, DDX3X, DDX5, DDX19, DDX21, DDX39B, DDX41. For each helicase, we reviewed evidence supporting their role genome suggested mechanisms. Such regulate expression factors promoting stability, prevent DNA damage, can participate directly response repair damage. Finally, summarized pathological therapeutic relationship cancer with respect to novel stability.

Язык: Английский

---

DDX41 is required for cGAS-STING activation against DNA virus infection

Cell Reports, Год журнала: 2022, Номер 39(8), С. 110856 - 110856

Опубликована: Май 1, 2022

Upon binding double-stranded DNA (dsDNA), cyclic GMP-AMP synthase (cGAS) is activated and initiates the cGAS-stimulator of IFN genes (STING)-type I interferon pathway. DEAD-box helicase 41 (DDX41) a helicase, mutations in DDX41 cause myelodysplastic syndromes (MDSs) acute myeloid leukemia (AML). Here, we show that DDX41-knockout (KO) cells have reduced type production after virus infection. Unexpectedly, activations cGAS STING are affected KO cells, suggesting functions upstream cGAS. The recombinant protein exhibits ATP-dependent DNA-unwinding activity ATP-independent strand-annealing activity. MDS/AML-derived mutant R525H has unwinding but retains normal stimulates greater dinucleotide-synthesis than wild-type DDX41. Overexpression either DDX41-deficient or -proficient results higher production. Our led to hypothesis utilizes its annealing activities regulate homeostasis dsDNA single-stranded (ssDNA), which, turn, regulates cGAS-STING activation.

Язык: Английский

---

DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1

Cell Reports, Год журнала: 2022, Номер 40(3), С. 111089 - 111089

Опубликована: Июль 1, 2022

Highlights•The helicase DDX18 mediates homeostasis of the DNA:RNA hybrids known as R loops•The function in R-loop is dependent on PARP-1•DDX18 C terminus required for poly(ADP-ribose) chain interaction at DNA-damage sites•DDX18 R-loop-induced DNA damage and genome integritySummaryR loops occur frequently genomes contribute to fundamental biological processes multiple levels. Consequently, understanding molecular cellular biology has become an emerging area research. Here, it shown that polymerase-1 (PARP-1) can mediate association DDX18, a putative RNA helicase, with thereby modulating endogenous R-loop-prone lesion regions. depletion results aberrant accumulation, which leads DNA-replication defects. In addition, renders cells more sensitive DNA-damaging agents reduces RPA32 RAD51 foci formation response irradiation. Notably, γH2AX accumulation instability, RNase H1 overexpression rescues all DNA-repair defects caused by depletion. Taken together, these studies uncover R-loop-mediated events suggest role PARP-1 mediating binding specific DDX-family proteins cells.Graphical abstract

Язык: Английский

---

Secondary structures in RNA synthesis, splicing and translation

Computational and Structural Biotechnology Journal, Год журнала: 2022, Номер 20, С. 2871 - 2884

Опубликована: Янв. 1, 2022

Even though the functional role of mRNA molecules is primarily decided by nucleotide sequence, several properties are determined secondary structure conformations. Examples structures include long range interactions, hairpins, R-loops and G-quadruplexes they formed through interactions non-adjacent nucleotides. Here, we discuss advances in our understanding how can impact RNA synthesis, splicing, translation half-life. During determine polymerase II (RNAPII) speed, thereby influencing splicing. Splicing also binding proteins their rates modulated structures. For initiation translation, control choice start site. highlight mechanisms which modulate these processes, technologies to detect study them systematically, consider roles disease.

Язык: Английский

---

DDX41-associated susceptibility to myeloid neoplasms

Blood, Год журнала: 2022, Номер 141(13), С. 1544 - 1552

Опубликована: Дек. 1, 2022

Deleterious germ line DDX41 variants confer risk for myeloid neoplasms (MNs) and less frequently lymphoid malignancies, with autosomal dominant inheritance an estimated prevalence of 3% among MNs. Germ include truncating alleles that comprise about two-thirds all alleles, missense located preferentially within the DEAD-box domain, deletion variants. The identification a allele on tumor-based molecular profiling should prompt genetic testing because >95% such are line. Somatic mutation wild-type occurs in half MNs typically exons encoding helicase domain most as R525H. Several aspects deleterious noteworthy: (1) certain common particular populations, (2) develop at older ages typical de novo disease, challenging paradigm inherited cancer always causes disease young people, (3) despite equal frequencies these men women, progress to more frequently, suggesting gender-specific effect leukemogenesis, (4) individuals acute severe graft-versus-host after allogeneic hematopoietic cell transplantation donors than others unless they receive posttransplant cyclophosphamide, proinflammatory milieu stimulates donor-derived T cells. Biochemical studies animal models have identified DDX41's ability interact double-stranded DNA RNA:DNA hybrids roles messenger RNA splicing, ribosomal RNAs or small nucleolar processing, modulation innate immunity, disruption which could promote inflammation drive tumorigenesis.

Язык: Английский

---