Recruitment of DNA polymerase eta by FANCD2 in the early response to DNA damage

Fu, Dianzheng; Dudimah, Fred Duafalia; Zhang, Jun; Pickering, Anna; Paneerselvam, Jayabal; Palrasu, Manikandan; Wang, Hong; Fei, Peiwen

doi:10.4161/cc.23755

Cited by 48 publications

(50 citation statements)

References 42 publications

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“…32,33 FANCD2-Ub also interacts with the TLS polymerase eta. 34 Unmodified FANCD2 is also required for chromatin loading of Blm, 35 and functionally interacts with FANCJ [36][37][38] and PCNA. 39 Among these functions of FANCD2, the recruitment of CtIP to the DSB ends would have significant effects on the HR repair, as the CtIP-induced DSB end resection is the initiating event of the HR repair process.…”

Section: Discussionmentioning

confidence: 99%

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

et al. 2016

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USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interactiondeficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.

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Section: Discussionmentioning

confidence: 99%

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

et al. 2016

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“…The modified FANCD2 colocalizes with factors that mediate DNA homologous recombination such as RAD51 and BRCA1 and FANCD2 may physically interact with BRCA2 at the chromatin (1,9,10). Monoubiquitinated FANCD2 also recruits ubiquitin zinc finger domain-containing DNA repair proteins such as FAN1, FANCP (SLX4), and translesion synthesis polymerases (11)(12)(13)(14)(15)(16). Therefore, monoubiquitination of FANCD2 by the FA E3 ligase complex is a critical regulatory step in the response to DNA damaging agents.…”

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confidence: 99%

The Carboxyl Terminus of FANCE Recruits FANCD2 to the Fanconi Anemia (FA) E3 Ligase Complex to Promote the FA DNA Repair Pathway

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Cukras

Wang

et al. 2014

Journal of Biological Chemistry

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“…Consistently, DNA polymerases h and z are recruited to DNA damage sites by FANCD2 in human cells and Xenopus egg extracts, respectively. 45,46 Further investigations are warranted to further address roles of TLS polymerases at acetaldehyde-mediated DNA adducts.…”

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confidence: 99%

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

et al. 2016

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Acetaldehyde, a primary metabolite of alcohol, forms DNA adducts and disrupts the DNA replication process, causing genomic instability, a hallmark of cancer. Indeed, chronic alcohol consumption accounts for approximately 3.6% of all cancers worldwide. However, how the adducts are prevented and repaired after acetaldehyde exposure is not well understood. In this report, we used the fission yeast Schizosaccharomyces pombe as a model organism to comprehensively understand the genetic controls of DNA damage avoidance in response to acetaldehyde. We demonstrate that Atd1 functions as a major acetaldehyde detoxification enzyme that prevents accumulation of Rad52-DNA repair foci, while Atd2 and Atd3 have minor roles in acetaldehyde detoxification. We found that acetaldehyde causes DNA damage at the replication fork and activates the cell cycle checkpoint to coordinate cell cycle arrest with DNA repair. Our investigation suggests that acetaldehyde-mediated DNA adducts include interstrand-crosslinks and DNA-protein crosslinks. We also demonstrate that acetaldehyde activates multiple DNA repair pathways. Nucleotide excision repair and homologous recombination, which are both epistatically linked to the Fanconi anemia pathway, have major roles in acetaldehyde tolerance, while base excision repair and translesion synthesis also contribute to the prevention of acetaldehyde-dependent genomic instability. We also show the involvement of Wss1-related metalloproteases, Wss1 and Wss2, in acetaldehyde tolerance. These results indicate that acetaldehyde causes cellular stresses that require cells to coordinate multiple cellular processes in order to prevent genomic instability. Considering that acetaldehyde is a human carcinogen, our genetic studies serve as a guiding investigation into the mechanisms of acetaldehyde-dependent genomic instability and carcinogenesis.

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Recruitment of DNA polymerase eta by FANCD2 in the early response to DNA damage

Cited by 48 publications

References 42 publications

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

The Carboxyl Terminus of FANCE Recruits FANCD2 to the Fanconi Anemia (FA) E3 Ligase Complex to Promote the FA DNA Repair Pathway

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

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