ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms

Cell Reports, Год журнала: 2023, Номер 42(7), С. 112792 - 112792

Опубликована: Июль 1, 2023

The ATR kinase safeguards genomic integrity during S phase, but how protects DNA replication forks remains incompletely understood. Here, we combine four distinct assays to analyze functions at ongoing and newly assembled upon inhibition by hydroxyurea. At forks, inhibitor (ATRi) increases MRE11- EXO1-mediated nascent degradation from PrimPol-generated, single-stranded (ssDNA) gaps. ATRi also exposes template ssDNA through fork uncoupling degradation. Electron microscopy reveals that reduces reversed increasing gap-dependent new triggers CtIP-initiated EXO1, exposing ssDNA. Upon PARP inhibition, preferentially exacerbates in BRCA1/2-deficient cells disrupts the restored gap protection BRCA1-deficient, PARP-inhibitor-resistant cells. Thus, mechanisms, providing an extended view of ATR's stabilizing forks.

Язык: Английский

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Freedom to err: The expanding cellular functions of translesion DNA polymerases

Molecular Cell, Год журнала: 2023, Номер 83(20), С. 3608 - 3621

Опубликована: Авг. 24, 2023

Язык: Английский

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CARM1 arginine methyltransferase as a therapeutic target for cancer

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(9), С. 105124 - 105124

Опубликована: Авг. 1, 2023

Coactivator-associated arginine methyltransferase 1 (CARM1) is an that posttranslationally modifies proteins regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, coregulators transcription, splicing factors. CARM1 overexpressed in many different cancer types, often promotes factor programs are co-opted as drivers the transformed cell state, a process known addiction. Targeting these oncogenic pathways difficult but could be addressed by removing activity key coactivators on which they rely. ubiquitously expressed, its KO less detrimental embryonic development than deletion methyltransferases protein 5, suggesting therapeutic targeting may well tolerated. Here, we will summarize normal vivo functions have been gleaned from mouse studies, expand transcriptional regulated CARM1, finally highlight recent studies identified properties biological settings. This review meant to kindle interest human drug therapies there currently no inhibitors available for use clinical trials.

Язык: Английский

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An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 17, 2023

Abstract Activation of the KRAS oncogene is a source replication stress, but how this stress generated and it tolerated by cancer cells remain poorly understood. Here we show that induction G12V expression in untransformed triggers H3K27me3 HP1-associated chromatin compaction an RNA transcription dependent manner, resulting fork slowing cell death. Furthermore, elevated ATR necessary sufficient for tolerance -induced to expand stress-tolerant (RSTCs). PrimPol phosphorylated at Ser255, potential Chk1 substrate site, under promotes repriming maintain progression survival ATR/Chk1-dependent manner. However, ssDNA gaps are heterochromatin PrimPol-dependent repriming, leading genomic instability. These results reveal role ATR-PrimPol enabling precancerous survive KRAS-induced clonally with accumulation

Язык: Английский

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CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A

Protein & Cell, Год журнала: 2024, Номер 15(10), С. 744 - 765

Опубликована: Март 13, 2024

Coactivator-associated arginine methyltransferase 1 (CARM1) promotes the development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer. The function CARM1 in triple-negative cancer (TNBC) is still unclear requires further exploration. Here, we report that proliferation, epithelial-mesenchymal transition, stemness TNBC. upregulated multiple cancers its expression correlates with progression. Genome-wide analysis showed recruited by hypoxia-inducible factor-1 subunit (HIF1A) occupy promoters CDK4, Cyclin D1, β-Catenin, HIF1A, MALAT1, SIX1 critically involved cell cycle, HIF-1 signaling pathway, Wnt VEGF thereby modulating proliferation invasion TNBC cells. We demonstrated physically associated directly interacts HIF1A. Moreover, found ellagic acid, an inhibitor CARM1, can suppress inhibiting CDK4 expression. Our research has determined molecular basis carcinogenesis effective natural inhibitor, which may provide new ideas drugs for therapy.

Язык: Английский

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