Interplay between DNA polymerases β and λ in repair of oxidation DNA damage in chicken DT40 cells

Tano, Keizo; Nakamura, Jun; Asagoshi, Kenjiro; Arima, Hiroshi; Sonoda, Eiichiro; Braithwaite, Elena K.; Prasad, Rajendra; Buerstedde, Jean Marie; Takeda, Shunichi; Watanabe, Masami; Wilson, Samuel H.

doi:10.1016/j.dnarep.2007.01.011

Cited by 49 publications

(56 citation statements)

References 19 publications

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“…We conclude from these data that Pol ␤ can function independently of interaction with XRCC1 following oxidative DNA damage or, more likely, that another DNA polymerase can substitute for Pol ␤. For example, Pol , Pol , and Pol Q also are implicated in the cellular response to H 2 O 2 , and Pol Q has been reported to physically associate with XRCC1 (5,39,47,51,57). Alternatively, the long-patch repair DNA polymerases Pol ␦ and/or Pol ε might substitute for Pol ␤.…”

Section: Discussionmentioning

confidence: 99%

DNA 3′-Phosphatase Activity Is Critical for Rapid Global Rates of Single-Strand Break Repair following Oxidative Stress

Breslin

Caldecott

2009

Molecular and Cellular Biology

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Oxidative stress is a major source of chromosome single-strand breaks (SSBs), and the repair of these lesions is retarded in neurodegenerative disease. The rate of the repair of oxidative SSBs is accelerated by XRCC1, a scaffold protein that is essential for embryonic viability and that interacts with multiple DNA repair proteins. However, the relative importance of the interactions mediated by XRCC1 during oxidative stress in vivo is unknown. We show that mutations that disrupt the XRCC1 interaction with DNA polymerase ␤ or DNA ligase III fail to slow SSB repair in proliferating CHO cells following oxidative stress. In contrast, mutation of the domain that interacts with polynucleotide kinase/phosphatase (PNK) and Aprataxin retards repair, and truncated XRCC1 encoding this domain fully supports this process. Importantly, the impact of mutating the protein domain in XRCC1 that binds these end-processing factors is circumvented by the overexpression of wild-type PNK but not by the overexpression of PNK harboring a mutated DNA 3-phosphatase domain. These data suggest that DNA 3-phosphatase activity is critical for rapid rates of chromosomal SSB repair following oxidative stress, and that the XRCC1-PNK interaction ensures that this activity is not rate limiting in vivo.Oxidative stress can have a major influence on genome integrity and cell survival and is an etiological factor in a number of neurological human diseases. Of these, several are associated with defects in the repair of DNA damage, including xeroderma pigmentosum (XP), ataxia telangiecatsia (A-T), ataxia oculomotor apraxia 1 (AOA1), and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) (1,28,34,37). The neuropathology evident in XP most likely reflects an inability to repair one or more single-strand oxidative adducts by nucleotide excision repair. In contrast, A-T is associated with cellular defects in the repair of DNA double-strand breaks (DSBs) and AOA1 and SCAN1 with defects in the repair of DNA single-strand breaks (SSBs). SSBs are the commonest DNA lesions arising in cells, and if they are not rapidly repaired they can inhibit transcription and/or generate replication-associated DSBs (3,26,59,60). The repair of oxidative SSBs involves DNA damage detection by PARP-1 followed by recruitment of the enzymes required for subsequent steps of the repair process, which include DNA end processing, DNA gap filling, and DNA ligation (9, 19). Many of the enzymes implicated in these steps interact physically with XRCC1, including DNA polynucleotide kinase (PNK) (54), Aprataxin (APTX) (13,14,18,31,44), DNA polymerase ␤ (Pol ␤) (10, 27), and DNA ligase III␣ (Lig3␣) (11,12). This has prompted the hypothesis that XRCC1 is a scaffold protein that recruits, stabilizes, and/or stimulates SSB repair (SSBR) enzymes at chromosomal SSBs, thereby accelerating the overall process (8, 9). While in vitro analyses generally are consistent with this idea, including the observation that XRCC1 mutation (50, 58), deletion (49), or depletion (6) retards the rate of chromos...

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Section: Discussionmentioning

confidence: 99%

DNA 3′-Phosphatase Activity Is Critical for Rapid Global Rates of Single-Strand Break Repair following Oxidative Stress

Breslin

Caldecott

2009

Molecular and Cellular Biology

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“…In this work, we compared the activities of DNA pol and DNA pol ␤, the 2 major SP-BER pols (22)(23), and showed that both DNA pol and DNA pol ␤ physically interact with RP-A (Fig. 2F), which, together with PCNA, reduced the efficiency of gap-filling by DNA pol ␤ in the presence of an 8-oxo-G lesion (Fig.…”

Section: Discussionmentioning

confidence: 99%

Replication protein A and proliferating cell nuclear antigen coordinate DNA polymerase selection in 8-oxo-guanine repair

Maga

Crespan

Wimmer

et al. 2008

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

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The adenine misincorporated by replicative DNA polymerases (pols) opposite 7,8-dihydro-8-oxoguanine (8-oxo-G) is removed by a specific glycosylase, leaving the lesion on the DNA. Subsequent incorporation of C opposite 8-oxo-G on the resulting 1-nt gapped DNA is essential for the removal of the 8-oxo-G to prevent G-C to T-A transversion mutations. By using model DNA templates, purified DNA pols ␤ and and knockout cell extracts, we show here that the auxiliary proteins replication protein A and proliferating cell nuclear antigen act as molecular switches to activate the DNA pol -dependent highly efficient and faithful repair of A:8-oxo-G mismatches in human cells and to repress DNA pol ␤ activity. By using an immortalized human fibroblast cell line that has the potential to induce cancer in mice, we show that the development of a tumoral phenotype in these cells correlated with a differential expression of DNA pols and ␤. R eactive oxygen species (ROS) are produced during normal cell metabolism and through the action of exogenous agents (1). When ROS react with DNA, the most frequently generated lesion (10 3 to 10 4 per cell per day) is 7,8-dihydro-8-oxoguanine (8-oxo-G) (2), whose mutagenic potential in aging, tumor transformation, and neurodegenerative diseases is well established. The presence of 8-oxo-G in the replicating strand can lead to frequent misincorporation of A opposite the lesion by the human replicative DNA polymerases (pols) ␣, ␦, and (3). Full repair of 8-oxo-G lesion is guaranteed by 2 different base excision repair (BER) systems: (i) an OGG1-dependent, which targets C:8-oxo-G mispairs, removes the lesion and leaves an intact DNA strand to act as template for the resynthesis step (4); and (ii) a MUTYH-dependent pathway, which targets the A:8-oxo-G base pair and removes the adenine (5-7). Subsequent error-free bypass of the lesion requires a specialized DNA pol that can catalyze the correct incorporation of C opposite 8-oxo-G during the resynthesis step, reconstituting a C:8-oxo-G base pair that could subsequently be repaired by the OGG1-dependent BER. However, the majority of human DNA pols insert an adenine opposite 8-oxo-G on the template strand with high frequencies (10-75% of the time). Thus, the molecular mechanism ensuring correct and efficient repair of A:8-oxo-G mismatches in human cells is currently undetermined.We have recently shown (8) that the BER enzyme DNA pol , which belongs to DNA pol family X (9), is very efficient in performing error-free translesion synthesis past the 2 major oxidative lesions 8-oxo-G (8) and 2-hydroxy-adenine (2-OH-A) (10). Moreover, its fidelity and efficiency is enhanced 2 orders of magnitude by the auxiliary proteins proliferating cell nuclear antigen (PCNA) and replication protein A (RP-A), both for normal and translesion synthesis, resulting in dATP incorporation frequencies opposite 8-oxo-G as low as 10 Ϫ3 . On the other hand, the other major BER enzyme DNA pol ␤ shows a relaxed nucleotide insertion specificity opposite 8-oxo-G, with erroneous (i.e., d...

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“…All DT40 mutants were derived from isogenic DT40 parent cell lines (Supplementary Table S1). The DT40 cells and their mutants were cultured as previously reported (8). Parental colorectal cancer cell lines (RKO) cells and isogenic clones harboring an engineered disruption of FANCC or FANCG (9) were cultured in a humidified 5% CO 2 atmosphere at 37jC.…”

Section: Methodsmentioning

confidence: 99%

Cells Deficient in the FANC/BRCA Pathway Are Hypersensitive to Plasma Levels of Formaldehyde

Ridpath¹,

et al. 2007

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Formaldehyde is an aliphatic monoaldehyde and is a highly reactive environmental human carcinogen. Whereas humans are continuously exposed to exogenous formaldehyde, this reactive aldehyde is a naturally occurring biological compound that is present in human plasma at concentrations ranging from 13 to 97 Mmol/L. It has been well documented that DNA-protein crosslinks (DPC) likely play an important role with regard to the genotoxicity and carcinogenicity of formaldehyde. However, little is known about which DNA damage response pathways are essential for cells to counteract formaldehyde. In the present study, we first assessed the DNA damage response to plasma levels of formaldehyde using chicken DT40 cells with targeted mutations in various DNA repair genes. Here, we show that the hypersensitivity to formaldehyde is detected in DT40 mutants deficient in the BRCA/ FANC pathway, homologous recombination, or translesion DNA synthesis. In addition, FANCD2-deficient DT40 cells are hypersensitive to acetaldehyde, but not to acrolein, crotonaldehyde, glyoxal, and methylglyoxal. Human cells deficient in FANCC and FANCG are also hypersensitive to plasma levels of formaldehyde. These results indicate that the BRCA/FANC pathway is essential to counteract DPCs caused by aliphatic monoaldehydes. Based on the results obtained in the present study, we are currently proposing that endogenous formaldehyde might have an effect on highly proliferating cells, such as bone marrow cells, as well as an etiology of cancer in

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Interplay between DNA polymerases β and λ in repair of oxidation DNA damage in chicken DT40 cells

Cited by 49 publications

References 19 publications

DNA 3′-Phosphatase Activity Is Critical for Rapid Global Rates of Single-Strand Break Repair following Oxidative Stress

DNA 3′-Phosphatase Activity Is Critical for Rapid Global Rates of Single-Strand Break Repair following Oxidative Stress

Replication protein A and proliferating cell nuclear antigen coordinate DNA polymerase selection in 8-oxo-guanine repair

Cells Deficient in the FANC/BRCA Pathway Are Hypersensitive to Plasma Levels of Formaldehyde

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