Translesion synthesis in mammalian cells

Lehmann, Alan R.

doi:10.1016/j.yexcr.2006.06.010

Cited by 102 publications

(73 citation statements)

References 36 publications

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“…Several lines of evidence have shown that PCNA monoubiquitination occurs both in yeast and higher eukaryotes, primarily in response to the DNA damage-induced stalling at DNA replication forks (13,(27)(28)(29). In the present study we have demonstrated that in addition to the monoubiquitination of PCNA, the chromatinbound PCNA polyubiquitination is enhanced by DNA damage that stalls DNA replication forks, but not by ␥-irradiation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

Motegi

Liaw

Lee

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

251

269

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C hronic stalling of DNA replication forks by DNA damage such as UV irradiation, ionizing irradiation, chemicals, and reactive cellular metabolites impedes the progression of the cell cycle and eventually causes cell death. To circumvent such situations, cells have evolved the postreplication repair (PRR) pathway that bypasses DNA lesions to resolve stalled forks without removing the actual damage (1). In budding yeast Saccharomyces cerevisiae, PRR is carried out by 2 distinct pathways: translesion synthesis (TLS) and template switching (TS) (Fig. 1A). TLS uses multiple low-fidelity TLS polymerases to incorporate nucleotides across DNA lesions (2, 3). Switching from replicative polymerases ␦ or to TLS polymerases is promoted through the interaction between monoubiquitinated PCNA at lysine 164 (K164) and a ubiquitin-binding motif in TLS polymerases-a mechanism conserved from the budding yeast to human. The monoubiquitination of PCNA at K164 requires the RING-type ubiquitin ligase Rad18 (E3) and the ubiquitinconjugating enzyme Rad6 (E2).The TS pathway bypasses DNA damage by switching a stalled replicating end to the nascent daughter strand of the sister chromatid (1, 4). This pathway involves a lysine 63 (K63)-linked polyubiquitin chain that is further added onto the monoubiquitinated PCNA by Rad5 (E3) along with the Ubc13-Mms2 (E2 and E2 variant, respectively) heterodimer complex (Fig. 1 A). Distinct from the K48-linked polyubiquitination leading to protein degradation, the K63-linked polyubiquitination of PCNA is thought to promote TS in a proteasome-independent manner (5).The importance of the TLS pathway in the suppression of mammalian tumorigenesis emerged with the identification of a mutation in TLS polymerase in patients with the variant form of xeroderma pigmentosum and from studies with mouse models (6, 7). Despite the presence of UBC13 and MMS2 homologues in humans, the importance of the TS pathway is less clear in mammals because K63-linked polyubiquitination of PCNA, a hallmark event for the TS pathway, had not been observed until recently (8-10). We recently identified human SHPRH, which possesses SWI2/SNF2 and RING domains with similar architecture to the yeast Rad5 as a functional homologue of yeast Rad5 (9). Specifically, we demonstrated the in vivo activity of SHPRH in promoting a K63-linked polyubiquitination of PCNA as well as physical interactions of SHPRH with PCNA, RAD18, and UBC13. Depletion of SHPRH increases genomic instability after genotoxic stress. Consistent with our work, another study also demonstrated that SHPRH could polyubiquitinate PCNA in vitro (11).In the present study, we demonstrated that ectopic expression of HLTF/SMARCA3/RUSH/HIP116/Zbu1 (hereafter, HLTF) enhanced PCNA polyubiquitination in vivo. Depletion of SHPRH or HLTF significantly reduced polyubiquitination of chromatin-bound PCNA upon treatment of cells with DNA-damaging agents that cause stalled DNA replication forks. Furthermore, Hltf-deficient mouse embryonic fibroblasts (MEFs) showed elevated chromosome breaks an...

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Section: Discussionmentioning

confidence: 99%

Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

Motegi

Liaw

Lee

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

251

269

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“…PCNA has recently been shown to be monoubiquitylated in response to UV light, which enhances its interaction with and activation of pol (57). PCNA was previously shown to interact with p300/CBP (cAMP-responsive element-binding protein-binding protein) histone acetyltransferase and may be acetylated (51,58).…”

Section: Discussionmentioning

confidence: 99%

Interaction of the Human DNA Glycosylase NEIL1 with Proliferating Cell Nuclear Antigen

Dou

Theriot

Das

et al. 2008

Journal of Biological Chemistry

129

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NEIL1 and NEIL2 compose a family of DNA glycosylases that is distinct from that of the other two DNA glycosylases, OGG1 and NTH1, all of which are involved in repair of oxidized bases in mammalian genomes. That the NEIL proteins, unlike OGG1 and NTH1, are able to excise base lesions from single-stranded DNA regions suggests their preferential involvement in repair during replication and/or transcription. Previous studies showing S phase-specific activation of NEIL1, but not NEIL2, suggested NEIL1 involvement in the repair of replicating DNA. Here, we show that human NEIL1 stably interacts both in vivo and in vitro with proliferating cell nuclear antigen (PCNA), the sliding clamp for DNA replication. PCNA stimulates NEIL1 activity in excising the oxidized base 5-hydroxyuracil from single-stranded DNA sequences including fork structures. PCNA enhances NEIL1 loading on the substrate. In contrast, although present in the NEIL2 immunocomplex, PCNA does not stimulate NEIL2. NEIL1 interacts with PCNA via a domain that is located in a region near the C terminus, dispensable for base excision activity. The interacting sequence in NEIL1, which lacks the canonical PCNA-binding motif, includes a sequence conserved in DNA polymerase ␦ and implicated in its PCNA binding. Mammalian two-hybrid analysis confirmed PCNA interaction with NEIL1. The G127A mutation in PCNA reduces its stimulatory activity, suggesting that the interdomain connector loop, a common binding interface of PCNA, is involved in NEIL1 binding. These results strongly support in vivo function of NEIL1 in preferential repair of oxidized bases in DNA prior to replication.Reactive oxygen species, ubiquitous genotoxic agents, are continuously generated in vivo as by-products of respiration and are also produced as a result of metabolism of toxic agents or induced during inflammatory responses (1-3). Reactive oxygen species have been implicated in the etiology of a wide variety of diseases ranging from arthritis to cancer and also in aging (4). Reactive oxygen species induce a plethora of oxidatively damaged bases, abasic (apurinic/apyrimidinic (AP)) 5 sites, and strand breaks in the genome that, if left unrepaired, could lead to mutagenesis, apoptosis, senescence, and sporadic cancer (4). Such damage, with the exception of double strand breaks, is repaired primarily via the DNA base excision repair (BER) pathway (5).The BER pathway, first delineated in Escherichia coli, is initiated with excision of the damaged base by a DNA glycosylase. Oxidized base-specific glycosylases, all with intrinsic AP lyase activity, then cleave the DNA strand at the resulting AP site, generating a 3Ј-terminal deoxyribose phosphate or 3Ј-phosphate (6). After removal of this 3Ј-blocking group, the single nucleotide gap is filled in by a DNA polymerase, using the undamaged complementary strand as a template, and DNA ligase finally seals the nick to restore duplex DNA (5, 7). The oxidized base-specific DNA glycosylases have broad substrate specificity commensurate with the large number of s...

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“…PCNA is also listed as a BER DNA synthesis and ligation related protein and is modified in many ways, including phosphorylation, acetylation, SUMO and ubiquitin, as listed in Table III. There are many detailed reviews that characterize the varied post-translational modifications of PCNA and the impact of these modifications on PCNA-protein interactions [132][133][134].…”

Section: Ber Dna Synthesis and Ligation Proteinsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

387

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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Translesion synthesis in mammalian cells

Cited by 102 publications

References 36 publications

Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

Interaction of the Human DNA Glycosylase NEIL1 with Proliferating Cell Nuclear Antigen

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

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