Specialized DNA Polymerases, Cellular Survival, and the Genesis of Mutations

Friedberg, Errol C.; Wagner, Robert E.; Radman, Miroslav

doi:10.1126/science.1070236

Cited by 416 publications

(300 citation statements)

References 52 publications

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“…The deployment of TLS polymerases during replication ensures timely bypass of the diverse DNA lesions encountered by the replication fork. Although many TLS polymerases are intrinsically mutagenic, polη allows replication past UV-damaged bases with high fidelity [9][10][11] . Thus, a model has emerged in which polη binds to monoubiquitinated PCNA and ensures accurate (error-free) replicative bypass of UV lesions.…”

mentioning

confidence: 99%

Regulation of monoubiquitinated PCNA by DUB autocleavage

et al. 2006

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Monoubiquitination is a reversible post-translational protein modification that has an important regulatory function in many biological processes, including DNA repair. Deubiquitinating enzymes (DUBs) are proteases that are negative regulators of monoubiquitination, but little is known about their regulation and contribution to the control of conjugated-substrate levels. Here, we show that the DUB ubiquitin specific protease 1 (USP1) deubiquitinates the DNA replication processivity factor, PCNA, as a safeguard against error-prone translesion synthesis (TLS) of DNA. Ultraviolet (UV) irradiation inactivates USP1 through an autocleavage event, thus enabling monoubiquitinated PCNA to accumulate and to activate TLS. Significantly, the site of USP1 cleavage is immediately after a conserved internal ubiquitin-like diglycine (Gly-Gly) motif. This mechanism is reminiscent of the processing of precursors of ubiquitin and ubiquitin-like modifiers by DUBs. Our results define a regulatory mechanism for protein ubiquitination that involves the signal-induced degradation of an inhibitory DUB.Monoubiquitination is a highly regulated process that is conserved in all eukaryotes 1,2 and controls a broad range of cellular functions, including DNA repair. Protein monoubiquitination is a reversible post-translational event that can be influenced by the opposing activities of a ubiquitin E3 ligase and a deubiquitinating enzyme (DUB), similar to the regulation of protein phosphorylation by kinases and phosphatases 3,4 . Protein monoubiquitination regulates the rescue of stalled DNA replication forks -an important cellular process required for cell survival 5 . The E2 ubiquitin conjugating enzyme RAD6 and the E3 ligase RAD18 are conserved in both yeast and human and they coordinate and activate the monoubiquitination of PCNA in response to UV damage or stalled replication forks [6][7][8] . Recent studies have shown that polη, a specialized TLS polymerase, is recruited to the replication fork through a specific interaction with monoubiquitinated PCNA 7 . The deployment of TLS polymerases during replication ensures timely bypass of the diverse DNA lesions encountered by the replication fork. Although many TLS polymerases are intrinsically mutagenic, polη allows replication past UV-damaged bases with high fidelity 9-11 . Thus, a model has emerged in which polη binds to monoubiquitinated PCNA and ensures accurate (error-free) replicative bypass of UV lesions. However, other (error-prone) TLS polymerases (such as polι and Rev1) have recently been shown to rely on monoubiquitinated PCNA for their function 12,13 . How cells limit PCNA monoubiquitination and the unwanted deployment of polη and/or other error-prone TLS polymerases in the absence or presence of extrinsic DNA damage during the synthesis of DNA in S phase is not known.In humans, protein deubiquitination is controlled by a family of approximately 95 distinct DUB enzymes 14,15 but the function of most of these proteins is unknown. DUBs are cysteine proteases that cleave ubiquitin fro...

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Regulation of monoubiquitinated PCNA by DUB autocleavage

et al. 2006

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“…Bacteria use TLS polymerases to avoid irreversible replication blocks when other damage avoiding strategies have failed 7 . By so doing, mutagenesis is favoured over cell death, and it has been widely discussed that mutator phenotypes have an adaptive value in prokaryotes 118,119 .…”

Section: Resultsmentioning

confidence: 99%

“…These non-replicative functions concern the removal and repair of damaged bases (for example, Polβ in baseexcision repair), the rejoining of broken DNA ends (Polλ and Polµ in non-homologous endjoining (NHEJ)), the by-pass of DNA lesions that block the progression of replication forks (Y family polymerases, as well as Polζ, in translesion DNA synthesis (TLS)) and templateindependent insertion of nucleotides (TdT during V(D)J recombination). One hypothesis proposed for the striking increase in the number of non-replicative polymerases in higher vertebrates compared with prokaryotes is that each polymerase would display a preferential handling of specific DNA lesions, for which it would harbour both higher efficiency and accuracy, thereby reducing the deleterious consequences of the corresponding damage 7 .…”

Section: Dna Polymerasesmentioning

confidence: 99%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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PrefaceTo cope with an unpredictable variety of potential pathogenic insults, the immune system must generate an enormous diversity of recognition structures, and it does so by making stepwise modifications of key genetic loci in each lymphoid cell. This proceeds through the action of lymphoid-specific proteins acting together with the general DNA-repair machinery of the cell. Strikingly, these general mechanisms are usually diverted from their normal functions, being used in rather atypical ways in order to privilege diversity over accuracy. In this Review, we focus on the contribution of a set of DNA polymerases discovered in the last decade to these unique DNA transactions.

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“…Thus, cell division in adult somatic tissues appears to put organisms at risk for developing cancer. This is not surprising, given that we now know that DNA replication puts cells at endanger for acquiring and fixing mutations (Kunkel and Bebenek, 2000;van Brabant et al, 2000;Friedberg et al, 2002;Thompson and Schild, 2002), and that somatic mutations are a major cause of cancer (Bishop, 1995;Simpson and Camargo, 1998;Gray and Collins, 2000;Knudson, 2000).…”

Section: Cancer and Age-related Diseasementioning

confidence: 99%

Aging, tumor suppression and cancer: high wire-act!

Campisi

2005

Mechanisms of Ageing and Development

154

120

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Evolutionary theory holds that aging is a consequence of the declining force of natural selection with age. We discuss here the evidence that among the causes of aging in complex multicellular organisms, such as mammals, is the antagonistically pleiotropic effects of the cellular responses that protect the organism from cancer. Cancer is relatively rare in young mammals, owing in large measure to the activity of tumor suppressor mechanisms. These mechanisms either protect the genome from damage and/or mutations, or they elicit cellular responsesapoptosis or senescence-that eliminate or prevent the proliferation of somatic cells at risk for neoplastic transformation. We focus here on the senescence response, reviewing its causes, regulation and effects. In addition, we describe recent data that support the idea that both senescence and apoptosis may indeed be the double-edged swords predicted by the evolutionary hypothesis of antagonistic pleiotropyprotecting organisms from cancer early in life, but promoting aging phenotypes, including late life cancer, in older organisms. # 2004 Published by Elsevier Ireland Ltd.

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Specialized DNA Polymerases, Cellular Survival, and the Genesis of Mutations

Cited by 416 publications

References 52 publications

Regulation of monoubiquitinated PCNA by DUB autocleavage

Regulation of monoubiquitinated PCNA by DUB autocleavage

DNA polymerases in adaptive immunity

Aging, tumor suppression and cancer: high wire-act!

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