APLF promotes the assembly and activity of non-homologous end joining protein complexes

Grundy, Gabrielle J.; Rulten, Stuart L.; Zeng, Zhihong; Arribas-Bosacoma, Raquel; Iles, Natasha; Manley, Katie; Oliver, Antony W.; Caldecott, Keith W.

doi:10.1038/emboj.2012.304

Cited by 126 publications

(176 citation statements)

References 45 publications

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“…APLF, also known as Xip1, is a recently discovered DNA repair protein with two C-terminal PBZ domains, which are required for the recruitment of APLF to sites of DNA damage (31,32). Interestingly, APLF is known to associate with core NHEJ components such as XRCC4-DNA ligase IV and Ku proteins (33)(34)(35). It is thus tempting to speculate that the augmented Ku protein recruitment to chromatin by increased PARP-1 expression in human cancer cells may be via association with APLF that binds to the abundant PARylated chromatin via its PBZ domain carrying Ku.…”

Section: Discussionmentioning

confidence: 99%

FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1

Dong

Wang

et al. 2016

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

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Fatty acid synthase (FASN), the sole cytosolic mammalian enzyme for de novo lipid synthesis, is crucial for cancer cell survival and associates with poor prognosis. FASN overexpression has been found to cause resistance to genotoxic insults. Here we tested the hypothesis that FASN regulates DNA repair to facilitate survival against genotoxic insults and found that FASN suppresses NF-κB but increases specificity protein 1 (SP1) expression. NF-κB and SP1 bind to a composite element in the poly(ADP-ribose) polymerase 1 (PARP-1) promoter in a mutually exclusive manner and regulate PARP-1 expression. Up-regulation of PARP-1 by FASN in turn increases Ku protein recruitment and DNA repair. Furthermore, lipid deprivation suppresses SP1 expression, which is able to be rescued by palmitate supplementation. However, lipid deprivation or palmitate supplementation has no effect on NF-κB expression. Thus, FASN may regulate NF-κB and SP1 expression using different mechanisms. Altogether, we conclude that FASN regulates cellular response against genotoxic insults by up-regulating PARP-1 and DNA repair via NF-κB and SP1.fatty acid synthase | transcription regulation | DNA repair | drug resistance | radiation resistance F atty acid synthase (FASN) is the key mammalian enzyme required for de novo synthesis of palmitate. FASN expression and activity are largely suppressed by sufficient dietary fat in most normal nonadipose tissues but are abnormally elevated in many human cancers and associated with poor prognosis (1). FASN association with poor prognosis may derive in part from FASN function in drug resistance during chemotherapy. Indeed, it has been found that FASN expression and/or activity was increased in drug-selected and -resistant breast (2) and pancreatic (3) cancer cells. It was also found that FASN overexpression causes cellular resistance to DNA-damaging drugs such as doxorubicin and mitoxantrone but not to microtubule modulators such as vinblastine and paclitaxel (4). Decreased ceramide production following doxorubicin treatment via suppression of tumor necrosis factor (TNF)-α production is believed to be one of the mechanisms of FASN-induced resistance to doxorubicin (4).The observation that FASN increases resistance to genotoxic drugs prompted us to hypothesize that FASN overexpression may up-regulate DNA damage response/repair pathways. In this study, we tested this hypothesis with a focus on the repair of DNA double-strand breaks (DSBs), which are commonly induced by the anticancer drugs doxorubicin and mitoxantrone and ionizing radiation. In mammalian cells, DSBs are repaired mainly via homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. NHEJ is the predominant form of DSB repair because it occurs during all phases of the cell cycle whereas HR only initiates at late G1 and S phases (5). Hence, we examined NHEJ repair of DSBs and found that FASN up-regulates NHEJ activity and repair of DSBs by increasing poly(ADP-ribose) polymerase 1 (PARP-1) expression via increasing the expression of spec...

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Section: Discussionmentioning

confidence: 99%

FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1

Dong

Wang

et al. 2016

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

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“…All these components interact with XRCC4 while PNK adds a phosphate to a 5=-OH extremity and remove 3=-phosphate groups. To avoid failed ligation, APTX plays an important role in deadenylation of the remaining AMP group at the 5= end, and APLF acts as an endonuclease and a 3=-exonuclease (100,104,105). Likewise, the cleavage triggers loss of genetic information while the gaps are filled by PolX family polymerases and .…”

Section: Nonhomologous End Joiningmentioning

confidence: 99%

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

Genois

Paquet

Laffitte

et al. 2014

Microbiol Mol Biol Rev

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SUMMARY All living organisms are continuously faced with endogenous or exogenous stress conditions affecting genome stability. DNA repair pathways act as a defense mechanism, which is essential to maintain DNA integrity. There is much to learn about the regulation and functions of these mechanisms, not only in human cells but also equally in divergent organisms. In trypanosomatids, DNA repair pathways protect the genome against mutations but also act as an adaptive mechanism to promote drug resistance. In this review, we scrutinize the molecular mechanisms and DNA repair pathways which are conserved in trypanosomatids. The recent advances made by the genome consortiums reveal the complete genomic sequences of several pathogens. Therefore, using bioinformatics and genomic sequences, we analyze the conservation of DNA repair proteins and their key protein motifs in trypanosomatids. We thus present a comprehensive view of DNA repair processes in trypanosomatids at the crossroads of DNA repair and drug resistance.

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“…2), but considering the number of nucleases present in the cell, it seems likely that other nucleases could be employed at incompatible ends, especially when Artemis is not present. Among those suggested to be involved in DSB repair include APLF, which is an abbreviation for Aprataxin and PNKP-like factor (also known as PALF) (39)(40)(41), flap structurespecific endonuclease 1 (FEN1), DNA replication helicase/nuclease 2 (DNA2), and exonuclease 1 (EXO1). In addition to nucleases, the Werner syndrome ATP-dependent helicase/nuclease (WRN) and the Bloom syndrome RecQ-like helicase (BLM) may also be involved in processing of DSB ends by creating a cleavage substrate for several of the aforementioned nucleases (42)(43)(44).…”

Section: Overview Of Nhej In Humans and Its Relationship With Other Pmentioning

confidence: 99%

Nonhomologous DNA end-joining for repair of DNA double-strand breaks

Pannunzio

Watanabe

Lieber

2018

Journal of Biological Chemistry

385

360

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Nonhomologous DNA end joining (NHEJ) is the predominant DSB repair pathway throughout the cell cycle and accounts for nearly all DSB repair outside of the S and G2 phases. NHEJ relies on Ku to thread onto DNA termini and thereby improve the affinity of the NHEJ enzymatic components consisting of polymerases (Pol m and Pol l), a nuclease (the Artemis·DNA-PKcs complex), and a ligase (XLF·XRCC4·Lig4 complex). Each of the enzymatic components is distinctive for its versatility in acting on diverse incompatible DNA end configurations coupled with a flexibility in loading order, resulting in many possible junctional outcomes from one DSB. DNA ends can either be directly ligated or, if the ends are incompatible, processed until a ligatable configuration is achieved that is often stabilized by up to 4 bp of terminal microhomology. Processing of DNA ends results in nucleotide loss or addition, explaining why DSBs repaired by NHEJ are rarely restored to their original DNA sequence. Thus, NHEJ is a single pathway with multiple enzymes at its disposal to repair DSBs, resulting in a diversity of repair outcomes.

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APLF promotes the assembly and activity of non-homologous end joining protein complexes

Cited by 126 publications

References 45 publications

FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1

FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

Nonhomologous DNA end-joining for repair of DNA double-strand breaks

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