PCNA Deubiquitylases Control DNA Damage Bypass at Replication Forks

Alvarez, Vanesa; Frattini, Camilla; Sacristán, María P.; Gallego-Sánchez, Alfonso; Bermejo, Rodrigo; Bueno, Avelino

doi:10.1016/j.celrep.2019.09.054

Cited by 16 publications

(47 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PCNA is ubiquitinated in response to DNA damage, but the level of ubiquitination generally observed (our study and ( 16 )) is rather low, with free-PCNA remaining predominant. Even in the absence of deubiquitylases, free-PCNA remains highly majoritarian ( 34 ). Given the low level of PCNA ubiquitination that is generally observed for S. cerevisiae , we can hypothesize that de novo ubiquitination occurs at each encounter with a lesion.…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic stress–induced mutagenesis is limited by a local control of translesion synthesis

Masłowska¹,

Villafañez²,

Laureti³

et al. 2022

Nucleic Acids Research

View full text Add to dashboard Cite

The DNA damage response (DDR) preserves the genetic integrity of the cell by sensing and repairing damages after a genotoxic stress. Translesion Synthesis (TLS), an error-prone DNA damage tolerance pathway, is controlled by PCNA ubiquitination. In this work, we raise the question whether TLS is controlled locally or globally. Using a recently developed method that allows to follow the bypass of a single lesion inserted into the yeast genome, we show that (i) TLS is controlled locally at each individual lesion by PCNA ubiquitination, (ii) a single lesion is enough to induce PCNA ubiquitination and (iii) PCNA ubiquitination is imperative for TLS to occur. More importantly, we show that the activation of the DDR that follows a genotoxic stress does not increase TLS at individual lesions. We conclude that unlike the SOS response in bacteria, the eukaryotic DDR does not promote TLS and mutagenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Eukaryotic stress–induced mutagenesis is limited by a local control of translesion synthesis

Masłowska¹,

Villafañez²,

Laureti³

et al. 2022

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…This rapid deubiqui>na>on could explain the low level of PCNA ubiqui>na>on generally observed upon genotoxic stress (this study and ( 16)). Indeed, the level of Ub-PCNA increases when the deubiquitylases are inac>vated (32).…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic stress induced mutagenesis is limited by a local control of Translesion Synthesis

Masłowska

Villafañez

Laureti

et al. 2021

Preprint

View full text Add to dashboard Cite

The DNA Damage Response (DDR) preserves the genetic integrity of the cell by sensing and repairing damages after a genotoxic stress. Translesion Synthesis (TLS), an error-prone DNA damage tolerance pathway, is controlled by PCNA ubiquitination. In this report, we raise the question whether TLS is controlled locally, or globally. Using a recently developed method that allows to follow the bypass of a single lesion inserted into the yeast genome, we show that: i) TLS is controlled locally at each individual lesion by PCNA ubiquitination, ii) a single lesion is enough to induce PCNA ubiquitination, and iii) PCNA ubiquitination is an absolute requirement for TLS to occur. More importantly, we show that global PCNA ubiquitination that follows a genotoxic stress does not increase TLS at individual lesions. We conclude that unlike the SOS response in bacteria, the eukaryotic DDR does not promote TLS and mutagenesis.

show abstract

“…The role of ubiquitin and SUMO modifications in DNA replication has been reviewed [162]. TLS-mediated DNA synthesis is downregulated and prevented at replication forks through PCNA deubiquitylation, most likely as a consequence of low TLS fidelity [163]. Significantly, it has been shown that PCNA ubiquitylation can operate after bulk genome replication, and, therefore, TLS DNA polymerases can effectively promote the error-prone DNA synthesis of ssDNA tracks late in G2 [164,165].…”

Section: Dna Synthesis Of Under-replicated Dna Tracks Prior To Mitosismentioning

confidence: 99%

Working on Genomic Stability: From the S-Phase to Mitosis

Ovejero

Bueno

Sacristán

2020

Genes

Self Cite

View full text Add to dashboard Cite

Fidelity in chromosome duplication and segregation is indispensable for maintaining genomic stability and the perpetuation of life. Challenges to genome integrity jeopardize cell survival and are at the root of different types of pathologies, such as cancer. The following three main sources of genomic instability exist: DNA damage, replicative stress, and chromosome segregation defects. In response to these challenges, eukaryotic cells have evolved control mechanisms, also known as checkpoint systems, which sense under-replicated or damaged DNA and activate specialized DNA repair machineries. Cells make use of these checkpoints throughout interphase to shield genome integrity before mitosis. Later on, when the cells enter into mitosis, the spindle assembly checkpoint (SAC) is activated and remains active until the chromosomes are properly attached to the spindle apparatus to ensure an equal segregation among daughter cells. All of these processes are tightly interconnected and under strict regulation in the context of the cell division cycle. The chromosomal instability underlying cancer pathogenesis has recently emerged as a major source for understanding the mitotic processes that helps to safeguard genome integrity. Here, we review the special interconnection between the S-phase and mitosis in the presence of under-replicated DNA regions. Furthermore, we discuss what is known about the DNA damage response activated in mitosis that preserves chromosomal integrity.

show abstract

PCNA Deubiquitylases Control DNA Damage Bypass at Replication Forks

Cited by 16 publications

References 82 publications

Eukaryotic stress–induced mutagenesis is limited by a local control of translesion synthesis

Eukaryotic stress–induced mutagenesis is limited by a local control of translesion synthesis

Eukaryotic stress induced mutagenesis is limited by a local control of Translesion Synthesis

Working on Genomic Stability: From the S-Phase to Mitosis

Contact Info

Product

Resources

About