Control of DNA Damage Bypass by Ubiquitylation of PCNA

Ripley, Brittany M; Gildenberg, Melissa; Washington, M. Todd

doi:10.3390/genes11020138

Cited by 39 publications

(38 citation statements)

References 82 publications

(145 reference statements)

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“…The DNA damage-tolerance pathway that promotes the exchange between replicative and specialized polymerases at stalled forks is known as translesion DNA synthesis (TLS). The recruitment of specialized DNA polymerases to DNA is favored by the ubiquitination of PCNA, thus providing a docking point for ubiquitin-binding domains in specialized DNA polymerases [ 24 , 99 ]. Despite the average poor fidelity of specialized polymerases, certain TLS events are not mutagenic when using specific DNA lesions as replication templates.…”

Section: Cdk-independent Effect Of P21 Overexpression On Damaged Dmentioning

confidence: 99%

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

Mansilla

Vega

Calzetta

et al. 2020

Genes

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p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by γ irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments.

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Section: Cdk-independent Effect Of P21 Overexpression On Damaged Dmentioning

confidence: 99%

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

Mansilla

Vega

Calzetta

et al. 2020

Genes

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“…4B) (Beckmann et al, 2017). K63 chains are associated with NF-κB signaling which has diverse functions including innate immunity, DNA transcription, autophagocytosis (Tan et al, 2008;Wertz and Dixit, 2010), and proliferation of cell nuclear antigen (PCNA) (Ripley et al, 2020) that has previously been shown to act abnormally in CI-affected embryos (Landmann et al, 2009). A single amino acid mutation in the catalytic site of the Ulp1 prevents the breakdown of ubiquitin chains in vitro (Beckmann et al, 2017).…”

Section: Cifb Molecular Functionmentioning

confidence: 99%

Symbiont-Mediated Cytoplasmic Incompatibility: What have we Learned in 50 Years?

Shropshire¹,

Leigh²,

Bordenstein³

2020

Preprint

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Cytoplasmic incompatibility (CI) is the most common symbiont-induced reproductive manipulation. Specifically, symbiont-induced sperm modifications cause catastrophic mitotic defects in the fertilized embryo and ensuing lethality in crosses between symbiotic males and either aposymbiotic females or females harboring a different symbiont strain. However, if the female carries the same symbiont strain, then embryos develop properly, which imparts a relative fitness benefit to symbiont-transmitting mothers. Thus, CI drives maternally transmitted bacteria to high frequencies in arthropod species worldwide. In the past two decades, CI has experienced a boom in interest due in part to its (i) deployment in successful, worldwide efforts to reduce the spread of mosquito-borne diseases, (ii) causation by bacteriophage genes, cifA and cifB, that modify animal reproductive processes, and (iii) important impacts on incipient speciation. This review serves as a gateway to experimental, conceptual, and quantitative themes of CI and outlines significant gaps in our understanding of CI’s mechanism that are ripe for investigation from a diversity of subdisciplines in the life sciences.

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“…Ubiquitin is added to and removed from many proteins directly involved in DNA damage bypass. The proliferating cell nuclear antigen (PCNA) sliding clamp is one such substrate that has essential roles in normal replication as well as in TLS and TS [ 36 ]. Eukaryotic PCNA functions as a heterotrimeric protein, forming a ring-like structure through which dsDNA at the replication fork is encircled [ 37 ].…”

Section: Ubiquitin and Ubiquitin-like Modifiers In Dna Damage Bypamentioning

confidence: 99%

Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

Wilkinson

Mnuskin

Ashton

et al. 2020

Cancers

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Many endogenous and exogenous factors can induce genomic instability in human cells, in the form of DNA damage and mutations, that predispose them to cancer development. Normal cells rely on DNA damage bypass pathways such as translesion synthesis (TLS) and template switching (TS) to replicate past lesions that might otherwise result in prolonged replication stress and lethal double-strand breaks (DSBs). However, due to the lower fidelity of the specialized polymerases involved in TLS, the activation and suppression of these pathways must be tightly regulated by post-translational modifications such as ubiquitination in order to limit the risk of mutagenesis. Many cancer cells rely on the deregulation of DNA damage bypass to promote carcinogenesis and tumor formation, often giving them heightened resistance to DNA damage from chemotherapeutic agents. In this review, we discuss the key functions of ubiquitin and ubiquitin-like proteins in regulating DNA damage bypass in human cells, and highlight ways in which these processes are both deregulated in cancer progression and might be targeted in cancer therapy.

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Control of DNA Damage Bypass by Ubiquitylation of PCNA

Cited by 39 publications

References 82 publications

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

Symbiont-Mediated Cytoplasmic Incompatibility: What have we Learned in 50 Years?

Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

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