DNA breaks and chromosomal aberrations arise when replication meets base excision repair

Ensminger, Michael; Iloff, Lucie; Ebel, Christian; Nikolova, Teodora; Kaina, Bernd; Löbrich, Markus

doi:10.1083/jcb.201312078

Cited by 121 publications

(118 citation statements)

References 69 publications

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“…However, we show here that cells expressing XRCC1(R194W) fail to recruit LIG3 to the sites of BER and accumulate higher numbers of micronuclei after exposure to oxidative stress, a likely consequence of the persistence of repair intermediates. Efficient sealing of SSBs in chromosomal DNA during BER is indeed crucial for maintaining genome integrity (49,50). It has been previously observed that a defect in XRCC1 affects a postincision step, the single-strand break rejoining, probably due to a defect in LIG3 (51).…”

Section: Discussionmentioning

confidence: 99%

Interaction with OGG1 Is Required for Efficient Recruitment of XRCC1 to Base Excision Repair and Maintenance of Genetic Stability after Exposure to Oxidative Stress

Campalans

Moritz

Kortulewski

et al. 2015

Molecular and Cellular Biology

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XRCC1 is an essential protein required for the maintenance of genomic stability through its implication in DNA repair. The main function of XRCC1 is associated with its role in the single-strand break (SSB) and base excision repair (BER) pathways that share several enzymatic steps. We show here that the polymorphic XRCC1 variant R194W presents a defect in its interaction with the DNA glycosylase OGG1 after oxidative stress. While proficient for single-strand break repair (SSBR), this variant does not colocalize with OGG1, reflecting a defect in its involvement in BER. Consistent with a role of XRCC1 in the coordination of the BER pathway, induction of oxidative base damage in XRCC1-deficient cells complemented with the R194W variant results in increased genetic instability as revealed by the accumulation of micronuclei. These data identify a specific molecular role for the XRCC1-OGG1 interaction in BER and provide a model for the effects of the R194W variant identified in molecular cancer epidemiology studies. C ellular DNA is continuously exposed to oxidative stress arising from both endogenous and exogenous sources. As a consequence, lesions such as modified bases, abasic (AP) sites, and single-strand breaks (SSBs) are generated (1). One of the major base lesions induced by oxidative stress is 8-oxoguanine (8-oxoG), which is recognized and excised by a specific DNA glycosylase, OGG1, initiating the base excision repair (BER) pathway (2). The AP site produced by OGG1 DNA glycosylase activity is then cleaved by the AP endonuclease APE1, resulting in a SSB. The subsequent synthesis and ligation steps are carried out by polymerase ␤ (POL␤) and ligase 3 (LIG3), respectively, to restore an intact DNA molecule (3). SSBs can also be directly induced in genomic DNA, and most of the enzymatic steps required for their repair are common to the single-strand break repair (SSBR) and BER pathways. Besides the enzymes mentioned above, other proteins participate in the efficient repair of modified bases and SSBs. Of these proteins, XRCC1, which is essential for embryonic development in mice (4), is a protein with no known enzymatic activity that acts as a scaffolding platform for SSBR and BER activities (5, 6). Cells deficient in XRCC1 exhibit increased frequencies of sister chromatid exchanges and chromosomal rearrangements. XRCC1 function is based in its capacity to interact with multiple enzymes and DNA intermediates in various DNA repair pathways (7,8), coordinating the rate and sequence of the enzymatic activities and thus avoiding the exposure of toxic DNA intermediates to the cellular milieu (9). The various XRCC1 domains responsible for the interactions with BER or SSBR enzymes have been identified. XRCC1 is composed of three structured domains, interspaced by two flexible/nonstructured linkers (10) (see Fig. 1A). The NTD (N-terminal domain) is responsible for the interaction with POL␤ (11, 12), the BRCT1 (BRCA1 carboxyl-terminal protein interaction domain 1) is involved in the interaction with poly(ADP-ribose) polymer...

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Section: Discussionmentioning

confidence: 99%

Interaction with OGG1 Is Required for Efficient Recruitment of XRCC1 to Base Excision Repair and Maintenance of Genetic Stability after Exposure to Oxidative Stress

Campalans

Moritz

Kortulewski

et al. 2015

Molecular and Cellular Biology

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“…Evidence is less clear for the 314 involvement of other repair enzymes in PoDs, although the roles 315 of BER and NER in preventing adduct-induced mutations make 316 them likely candidates for low dose protection. fork [54,55]. Therefore, they require immediate further processing.…”

Section: Q2mentioning

confidence: 98%

“…In conclusion, from a theoretical perspective it is reasonable to posit that tolerance to low dose levels exists for each requisite step of tumor formation and these tolerance mechanisms are critical in determining thresholds in chemical carcinogenesis. chemicals have a number of barriers to traverse before a molecule 55 reaches the DNA target. Potential reaction with culture media and 56 cellular components (proteins and RNA) would reduce the 57 effective dose of administered chemical to reach and react with 58 DNA.…”

Section: Q2mentioning

confidence: 99%

Theoretical considerations for thresholds in chemical carcinogenesis

Thomas¹,

Fahrer²,

Johnson

et al. 2015

Mutation Research/Reviews in Mutation Research

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“…Such DSBs occur at appreciable frequencies endogenously when replication forks encounter spontaneous base damages and/or single-strand breaks but also arise from agents that induce such single-stranded lesions (Ensminger et al, 2014; Jeggo and Löbrich, 2015). In addition to their role in repairing one-ended DSBs, HR factors also exert important functions in protecting stalled replication forks and their absence leads to degradation of newly synthesized DNA (Branzei and Foiani, 2010; Schlacher et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Nek1 Regulates Rad54 to Orchestrate Homologous Recombination and Replication Fork Stability

et al. 2016

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SUMMARY Never-in-mitosis A-related kinase 1 (Nek1) has established roles in apoptosis and cell cycle regulation. We show that human Nek1 regulates homologous recombination (HR) by phosphorylating Rad54 at Ser572 in late G2 phase. Nek1 deficiency as well as expression of unphosphorylatable Rad54 (Rad54-S572A) cause unresolved Rad51 foci and confer a defect in HR. Phosphomimic Rad54 (Rad54-S572E), in contrast, promotes HR and rescues the HR defect associated with Nek1 loss. Although expression of phosphomimic Rad54 is beneficial for HR, it causes Rad51 removal from chromatin and degradation of stalled replication forks in S phase. Thus, G2-specific phosphorylation of Rad54 by Nek1 promotes Rad51 chromatin removal during HR in G2 phase, and its absence in S phase is required for replication fork stability. In summary, Nek1 regulates Rad51 removal to orchestrate HR and replication fork stability.

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DNA breaks and chromosomal aberrations arise when replication meets base excision repair

Abstract: DNA double-strand breaks and chromosomal aberrations after treatment with N-alkylating agents likely arise as a result of replication fork collision with single-strand breaks generated during base excision repair.

Cited by 121 publications

References 69 publications

Interaction with OGG1 Is Required for Efficient Recruitment of XRCC1 to Base Excision Repair and Maintenance of Genetic Stability after Exposure to Oxidative Stress

Interaction with OGG1 Is Required for Efficient Recruitment of XRCC1 to Base Excision Repair and Maintenance of Genetic Stability after Exposure to Oxidative Stress

Theoretical considerations for thresholds in chemical carcinogenesis

Nek1 Regulates Rad54 to Orchestrate Homologous Recombination and Replication Fork Stability

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