BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response

Molecular Cell, Год журнала: 2024, Номер 84(9), С. 1684 - 1698.e9

Опубликована: Апрель 8, 2024

Язык: Английский

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Epigenetic regulation in cancer

MedComm, Год журнала: 2024, Номер 5(2)

Опубликована: Фев. 1, 2024

Abstract Epigenetic modifications are defined as heritable changes in gene activity that do not involve the underlying DNA sequence. The oncogenic process is driven by accumulation of alterations impact genome's structure and function. Genetic mutations, which directly disrupt sequence, complemented epigenetic modulate expression, thereby facilitating acquisition malignant characteristics. Principals among these shifts methylation histone mark patterns, promote tumor development metastasis. Notably, reversible nature alterations, opposed to permanence genetic changes, positions machinery a prime target discovery novel therapeutics. Our review delves into complexities regulation, exploring its profound effects on initiation, metastatic behavior, metabolic pathways, microenvironment. We place particular emphasis dysregulation at each level modulation, including but limited to, aberrations enzymes responsible for modification, subunit loss or fusions chromatin remodeling complexes, disturbances higher‐order structure. Finally, we also evaluate therapeutic approaches leverage growing understanding dysregulation, offering new avenues cancer treatment.

Язык: Английский

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Rapid Detection and Signaling of DNA Damage by PARP-1

Trends in Biochemical Sciences, Год журнала: 2021, Номер 46(9), С. 744 - 757

Опубликована: Март 3, 2021

Язык: Английский

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The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells

Genes & Development, Год журнала: 2021, Номер 35(17-18), С. 1271 - 1289

Опубликована: Авг. 12, 2021

PARP inhibitor (PARPi) is widely used to treat BRCA1/2-deficient tumors, but why PARPi more effective than other DNA-damaging drugs unclear. Here, we show that generates DNA double-strand breaks (DSBs) predominantly in a trans cell cycle manner. During the first S phase after exposure, induces single-stranded (ssDNA) gaps behind replication forks. By trapping on DNA, prevents completion of gap repair until next phase, leading collisions forks with ssDNA and surge DSBs. In second cells are unable suppress origin firing through ATR, resulting continuous synthesis Furthermore, cannot recruit RAD51 collapsed Thus, DSBs progressively gaps, fail slow down over multiple cycles, explaining unique efficacy cells.

Язык: Английский

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The CIP2A–TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer

Nature Cancer, Год журнала: 2021, Номер 2(12), С. 1357 - 1371

Опубликована: Ноя. 11, 2021

Язык: Английский

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Exploiting synthetic lethality to target BRCA1/2-deficient tumors: where we stand

Oncogene, Год журнала: 2021, Номер 40(17), С. 3001 - 3014

Опубликована: Март 14, 2021

Язык: Английский

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Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification

Cancer Research, Год журнала: 2022, Номер 82(8), С. 1646 - 1657

Опубликована: Фев. 16, 2022

Abstract PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and breast, prostate, pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker HRR functionality, we previously established test to detect foci. Here, aimed validate the score cut off compare performance this other deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, PaC were developed evaluated their response PARPi cisplatin. HRD these patient samples was by DNA sequencing genes, genomic tests, detection. We patient-derived xenograft (n = 103), HGSOC 4), 2) that recapitulated status treatment response. The showed higher accuracy than gene mutations analysis predicting (95%, 67%, 71%, respectively). captured dynamic changes upon acquisition resistance. similar platinum predefined validated, high predictive value preclinical confirmed. These results collectively support pursuing clinical assessment randomized trials testing or platinum-based therapies. Significance: This work demonstrates histopathology-based based on

Язык: Английский

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Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation

Molecular Cell, Год журнала: 2022, Номер 82(7), С. 1297 - 1312.e8

Опубликована: Фев. 25, 2022

Synthetic lethality through combinatorial targeting DNA damage response (DDR) pathways provides exciting anticancer therapeutic benefit. Currently, the long noncoding RNAs (lncRNAs) have been implicated in tumor drug resistance; however, their potential significance DDR is still largely unknown. Here, we report that a human lncRNA, CTD-2256P15.2, encodes micropeptide, named PAR-amplifying and CtIP-maintaining micropeptide (PACMP), with dual function to maintain CtIP abundance promote poly(ADP-ribosyl)ation. PACMP not only prevents from ubiquitination inhibiting CtIP-KLHL15 association but also directly binds damage-induced poly(ADP-ribose) chains enhance PARP1-dependent Targeting alone inhibits growth by causing synthetic lethal interaction between PARP inhibitions confers sensitivity PARP/ATR/CDK4/6 inhibitors, ionizing radiation, epirubicin, camptothecin. Our findings reveal lncRNA-derived regulates cancer progression resistance modulating DDR, whose inhibition could be employed augment existing strategies.

Язык: Английский

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Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Frontiers in Genetics, Год журнала: 2022, Номер 13

Опубликована: Янв. 31, 2022

Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular DSBs encompass a range highly coordinated events designed detect and respond appropriately the damage, thereby preserving genomic integrity. In analogy with occurring during viral infection, we appropriate terms Immediate-Early, Early, Late describe pre-repair DSBs. A distinguishing feature Immediate-Early response is that large protein condensates form Early are resolved upon repair, termed foci, not visible. encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, MRN, as well rapid repair by so-called 'fast-kinetic' canonical non-homologous end joining (cNHEJ). Initial binding PARPs KU70/80 complex appears be mutually exclusive at easily ligatable repaired efficiently fast-kinetic cNHEJ; process PARP-, ATM-, 53BP1-, Artemis-, resection-independent. However, more requiring processing, ensuing dynamic PARylation (polyADP ribosylation) many substrates may aid recruitment both MRN Complex rely response, largely defined ATM-dependent focal signalling molecules into condensates, regulated chromatin dynamics. Finally, integrates cell cycle phase, context, type DSB determine pathway choice. Critical choice p53 1 (53BP1) breast cancer associated (BRCA1). additional factors recruited throughout also impact choice, although these remain fully characterised. somehow channels high-fidelity pathway, typically either 'slow-kinetic' cNHEJ homologous recombination (HR). specific components machinery results in cells utilising remaining effect but often cost increased mutagenesis. Here discuss regulation proceeding itself.

Язык: Английский

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The DNA damage response in the chromatin context: A coordinated process

Current Opinion in Cell Biology, Год журнала: 2023, Номер 82, С. 102176 - 102176

Опубликована: Июнь 1, 2023

In the cell nucleus, DNA damage signaling and repair machineries operate on a chromatin substrate, integrity of which is critical for function viability. Here, we review recent advances in deciphering tight coordination between maintenance response (DDR). We discuss how DDR impacts marks, organization mobility, and, turn, alterations actively contribute to DDR, providing additional levels regulation. present our current knowledge molecular bases these processes physiological pathological conditions, also highlight open questions that emerge this expanding field.

Язык: Английский

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