The BLM helicase is a new therapeutic target in multiple myeloma involved in replication stress survival and drug resistance DOI Creative Commons
Sara Ovejero,

Elena Viziteu,

Laure Dutrieux

и другие.

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Дек. 9, 2022

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments one major challenges this disease. The DNA helicase BLM, whose depletion or mutation causes cancer-prone Bloom’s syndrome (BS), central factor damage repair homologous recombination (HR) genomic stability maintenance. Using independent cohorts patients, we identified that high expression BLM associated with poor outcome significant enrichment replication stress signature. We provide evidence chemical inhibition small molecule ML216 HMCLs (human cell lines) leads cycle arrest increases apoptosis, likely damage. synergizes alkylating agent melphalan efficiently inhibit growth promote death HMCLs. Moreover, treatment re-sensitizes melphalan-resistant lines conventional therapeutic agent. Altogether, these data suggest combination damaging agents could be interest MM, especially those patients and/or melphalan.

Язык: Английский

Cyclin-dependent kinases in DNA damage response DOI Creative Commons
Mateusz Kciuk, Adrianna Gielecińska, Somdutt Mujwar

и другие.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2022, Номер 1877(3), С. 188716 - 188716

Опубликована: Март 7, 2022

The cyclin-dependent kinase (CDK) family plays a critical role in variety of signaling pathways that regulate transcription and cell-cycle progression. Recently, the CDKs DNA damage response (DDR) has emerged. affect both repair, contributing to fidelity cell division process as well maintenance genomic integrity following damage. This is due modulatory on double-strand break repair (DSBR) components, including their influence enzymes involved homologous recombination (HR) non-homologous end-joining (NHEJ). In this review, impact DDR discussed.

Язык: Английский

Процитировано

74
G-quadruplex DNA: a novel target for drug design DOI
Fangyuan Teng, Zongzhe Jiang, Man Guo

и другие.

Cellular and Molecular Life Sciences, Год журнала: 2021, Номер 78(19-20), С. 6557 - 6583

Опубликована: Авг. 30, 2021

Язык: Английский

Процитировано

90
The Chlamydomonas Genome Project, version 6: Reference assemblies for mating-type plus and minus strains reveal extensive structural mutation in the laboratory DOI Creative Commons
Rory J. Craig, Sean D. Gallaher, Shengqiang Shu

и другие.

The Plant Cell, Год журнала: 2022, Номер 35(2), С. 644 - 672

Опубликована: Дек. 23, 2022

Abstract Five versions of the Chlamydomonas reinhardtii reference genome have been produced over last two decades. Here we present version 6, bringing significant advances in assembly quality and structural annotations. PacBio-based chromosome-level assemblies for laboratory strains, CC-503 CC-4532, provide resources plus minus mating-type alleles. We corrected major misassemblies previous validated our via linkage analyses. Contiguity increased ten-fold >80% filled gaps are within genes. used Iso-Seq deep RNA-seq datasets to improve annotations, updated gene symbols textual annotation functionally characterized genes extensive manual curation. discovered that cell wall-less classical strain exhibits genomic instability potentially caused by deletion helicase RECQ3, with mutations identified affect >100 therefore CC-4532 as primary reference, although this also carries unique is experiencing rapid proliferation a Gypsy retrotransposon. expect all strains harbor gene-disrupting mutations, which should be considered when interpreting comparing experimental results. Collectively, presented here herald new era genomics will foundation continued research important organism.

Язык: Английский

Процитировано

62
Resistance to DNA repair inhibitors in cancer DOI Creative Commons
Joseph S. Baxter, Diana Zatreanu, Stephen J. Pettitt

и другие.

Molecular Oncology, Год журнала: 2022, Номер 16(21), С. 3811 - 3827

Опубликована: Май 14, 2022

The DNA damage response (DDR) represents a complex network of proteins which detect and repair damage, thereby maintaining the integrity genome preventing transmission mutations rearranged chromosomes to daughter cells. Faults in DDR are known driver hallmark cancer. Furthermore, inhibition enzymes can be used treat disease. This is exemplified by PARP inhibitors (PARPi) cancers with defects homologous recombination pathway. A series novel targets now also under pre‐clinical or clinical investigation, including ATR kinase, WRN helicase polymerase/helicase Polθ (Pol‐Theta). Drug resistance common phenomenon that impairs overall effectiveness cancer treatments there already some understanding how PARPi occurs. Here, we discuss an could inform new drugs targeting emerges. We potential strategies limit impact these therapy mechanisms

Язык: Английский

Процитировано

53
Therapeutic Targeting of DNA Replication Stress in Cancer DOI Open Access

Long Gu,

Robert J. Hickey,

Linda H. Malkas

и другие.

Genes, Год журнала: 2023, Номер 14(7), С. 1346 - 1346

Опубликована: Июнь 26, 2023

This article reviews the currently used therapeutic strategies to target DNA replication stress for cancer treatment in clinic, highlighting their effectiveness and limitations due toxicity drug resistance. Cancer cells experience enhanced spontaneous damage compromised machinery, elevated levels of reactive oxygen species, loss tumor suppressor genes, and/or constitutive activation oncogenes. Consequently, these are addicted response signaling pathways repair machinery maintain genome stability support survival proliferation. Chemotherapeutic drugs exploit this genetic instability by inducing additional overwhelm system cells. However, clinical use DNA-damaging agents is limited resistance often arises. To address issues, discusses a potential strategy cancer-associated isoform proliferating cell nuclear antigen (caPCNA), which plays central role network. Small molecule peptide that specifically caPCNA can selectively without significant normal or experimental animals.

Язык: Английский

Процитировано

17
KNO1‐mediated autophagic degradation of the Bloom syndrome complex component RMI1 promotes homologous recombination DOI Creative Commons
Po‐Yu Chen, Nancy De Winne, Geert De Jaeger

и другие.

The EMBO Journal, Год журнала: 2023, Номер 42(10)

Опубликована: Март 27, 2023

Abstract Homologous recombination (HR) is a key DNA damage repair pathway that tightly adjusted to the state of cell. A central regulator homologous conserved helicase‐containing Bloom syndrome complex, renowned for its crucial role in maintaining genome integrity. Here, we show Arabidopsis thaliana , complex activity controlled by selective autophagy. We find recently identified KNO1 facilitates K63‐linked ubiquitination RMI1, structural component thereby triggering RMI1 autophagic degradation and resulting increased recombination. Conversely, reduced makes plants hypersensitive damage. itself also at level proteolysis, this case mediated ubiquitin–proteasome system, becoming stabilized upon via two redundantly acting deubiquitinases, UBP12 UBP13. These findings uncover regulatory cascade interconnected protein steps fine‐tuned HR response

Язык: Английский

Процитировано

15
Positive and negative regulators of RAD51/DMC1 in homologous recombination and DNA replication DOI
Masaru Ito, Yurika Fujita, Akira Shinohara

и другие.

DNA repair, Год журнала: 2023, Номер 134, С. 103613 - 103613

Опубликована: Дек. 13, 2023

Язык: Английский

Процитировано

14
Premature aging in genetic diseases: what conclusions can be drawn for physiological aging DOI Creative Commons

Filip Milosic,

Markus Hengstschläger, Selma Osmanagic‐Myers

и другие.

Frontiers in Aging, Год журнала: 2024, Номер 4

Опубликована: Фев. 28, 2024

According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes cellular damage (genomic instability, telomere attrition, loss proteostasis, epigenetic alterations and compromised macroautophagy), antagonistic that represent response (deregulated nutrient sensing, senescence, mitochondrial dysfunction) integrative culprits phenotype (stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). In contrast aging, premature diseases are driven by one or two distinct such as genomic instability in case Werner syndrome (WS), each displaying other a variable extent. this review we will focus on well-investigated Hutchinson-Gilford progeria (HGPS), WS, Cockayne (CS) for provide an overview reported elucidate resemblance mechanistic level context characteristic age-related diseases. Ubiquitous tissue specific animal models discussed useful tools decipher fundamental aging-related mechanisms develop intervention strategies combat

Язык: Английский

Процитировано

6
Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair DOI Creative Commons
Jeremy M. Kelm,

Amirreza Samarbakhsh,

Athira Pillai

и другие.

Frontiers in Oncology, Год журнала: 2022, Номер 12

Опубликована: Апрель 6, 2022

The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course treatment, yet the efficacy these therapies is tempered by DNA repair and damage response (DDR) pathways. Aberrations in DDR are observed many subtypes can promote de novo carcinogenesis, genomic instability, ensuing resistance to current therapy. Additionally, stalled collapsed replication forks present a unique challenge double-strand break (DSB) system. Of various inducible lesions, DSBs most lethal thus desirable setting treatment. In mammalian cells, typically repaired error prone non-homologous end joining pathway (NHEJ) high-fidelity homology directed (HDR) pathway. Targeting DSB pathways using small molecular inhibitors offers promising mechanism synergize IR while selective inhibition NHEJ induce synthetic lethality HDR-deficient subtypes. Selective alternative DSB-repair may also see future use precision genome editing direct resulting created HDR this review, we highlight recent advances development non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members NHEJ, minor backup SSA alt-NHEJ described within review target non-PIKKs mediators including Ku70/80, Artemis, Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, polymerase θ. While PIKKs remain intensely pursued as therapeutic targets, molecule represents an emerging opportunity drug discovery that considerable potential impact

Язык: Английский

Процитировано

18
Design and synthesis of quinazolin-4-one derivatives as potential anticancer agents and investigation of their interaction with RecQ helicases DOI

Hanan S. Haggag,

Shaimaa M. Aboukhatwa, Mohamed S. Nafie

и другие.

Bioorganic Chemistry, Год журнала: 2024, Номер 144, С. 107086 - 107086

Опубликована: Янв. 4, 2024

Язык: Английский

Процитировано

4