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1.
Mol Cell ; 83(13): 2161-2163, 2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37419089

RESUMO

There has been growing appreciation that transcription is an endogenous source of replication stress and must be coordinated with replication. In this issue, Bhowmick et al.1 uncover a protective mechanism that prevents co-directional transcription-replication conflicts (TRCs) from becoming genotoxic.


Assuntos
Replicação do DNA , Transcrição Gênica , Dano ao DNA
2.
PLoS Genet ; 18(12): e1010309, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36480547

RESUMO

DNA replication is a vulnerable time for genome stability maintenance. Intrinsic stressors, as well as oncogenic stress, can challenge replication by fostering conflicts with transcription and stabilizing DNA:RNA hybrids. RAD18 is an E3 ubiquitin ligase for PCNA that is involved in coordinating DNA damage tolerance pathways to preserve genome stability during replication. In this study, we show that RAD18 deficient cells have higher levels of transcription-replication conflicts and accumulate DNA:RNA hybrids that induce DNA double strand breaks and replication stress. We find that these effects are driven in part by failure to recruit the Fanconi Anemia protein FANCD2 at difficult to replicate and R-loop prone genomic sites. FANCD2 activation caused by splicing inhibition or aphidicolin treatment is critically dependent on RAD18 activity. Thus, we highlight a RAD18-dependent pathway promoting FANCD2-mediated suppression of R-loops and transcription-replication conflicts.


Assuntos
Reparo do DNA , Anemia de Fanconi , Humanos , Reparo do DNA/genética , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , DNA/genética , Dano ao DNA/genética , Replicação do DNA/genética , RNA , Instabilidade Genômica/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo
3.
Proc Natl Acad Sci U S A ; 115(38): 9586-9591, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30185560

RESUMO

The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP-N-acetylglucosamine-1-P transferase (ALG7), a subunit of the 20S proteasome (PRE7), and YBR085C-A induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding.


Assuntos
Adaptação Fisiológica/genética , Aneuploidia , Estresse do Retículo Endoplasmático/genética , Regulação Fúngica da Expressão Gênica/fisiologia , Saccharomyces cerevisiae/fisiologia , Cromossomos Fúngicos/genética , Farmacorresistência Fúngica/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Dobramento de Proteína , Tunicamicina/farmacologia , Resposta a Proteínas não Dobradas/fisiologia
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