FANCD2 and CtIP Cooperate to Repair DNA Interstrand Crosslinks

Murina, Olga; Aesch, Christine von; Karakus, Ufuk; Ferretti, Lorenza P.; Bolck, Hella Anna; Hänggi, Kay; Sartori, Alessandro A.

doi:10.1016/j.celrep.2014.03.069

Cited by 77 publications

(157 citation statements)

References 45 publications

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“…[15][16][17] Single-stranded stretch of DNA is exposed by end resection and bound by ssDNA binding protein RPA (replication protein A), which is in turn displaced by RAD51. The ATR-mediated phosphorylation of RPA is generally used as a surrogate marker of activated RPA and the DSB end resection status.…”

Section: Resultsmentioning

confidence: 99%

“…FANCD2-Ub recruits FAN1 nuclease to stalled replication forks, 31 CtIP exonuclease to damaged sites and replication forks to regulate DSB end resection, [15][16][17] and XPF-ERCC1 to repair the replication-associated ICL lesions. 32,33 FANCD2-Ub also interacts with the TLS polymerase eta.…”

Section: Discussionmentioning

confidence: 99%

“…FANCD2 is required for efficient recruitment of CtIP, [15][16][17] an endonuclease that induces end resection at DSB sites to generate ssDNA, an important step that initiates the HR repair. Whether the role of USP1 and UAF1 in HR repair is limited to the FANCD2 and CtIP retention at the DSB sites, or whether there are other functions that directly regulate the HR repair proteins, is unknown.…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Monoubiquitination of FANCD2 and FANCI peaks during S phase of the cell cycle, which is consistent with the timing of HR and TLS events in the cell. The monoubiquitinated FANCD2 performs multiple functions in coordinating the downstream repair activities by recruiting the following: (i) FAN1 and XPF-ERCC nucleases to facilitate the incision process and unhooking of the cross-linked DNA segment (159)(160)(161)(162)(163)(164); (ii) TLS polymerase to facilitate replicative bypass of the unhooked ICL lesion (165); and (iii) exonuclease CtIP to induce 3=-to-5= resection of DSB DNA ends to generate ssDNA to channel the broken DNA ends to HRmediated repair (166)(167)(168). Although the requirement for monoubiquitinated FANCD2 is well established in replicationcoupled ICL repair, the receptor that interacts specifically with the monoubiquitinated form remains controversial and has yet to be identified.…”

Section: Dubs That Regulate Dna Replication-associated Dna Damage Resmentioning

confidence: 99%

Role of Deubiquitinating Enzymes in DNA Repair

Kee

Huang

2016

Molecular and Cellular Biology

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Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling. DEUBIQUITINATING ENZYMES Safeguarding the genome from genotoxic stress is critical for cell survival and for preventing various human diseases, including cancer. DNA repair or DNA damage responses are under exquisite control and must be accurately and rapidly executed when genome integrity is challenged. Understanding the molecular mechanisms and regulation of critical DNA repair and damage response factors in mammalian cells will provide insight into the pathogenesis of human diseases and aid in the development of therapeutics. Ubiquitination is a posttranslational modification event that allows for rapid and dynamic changes in a protein fate or function. The ubiquitin-proteasome system (UPS) is an essential posttranslational regulatory mechanism that permeates into diverse biological processes, including the DNA repair and damage response pathways. While the role of ubiquitin in mediating controlled degradation/proteolysis of specific proteins is well established, nonproteolytic functions of ubiquitination have also emerged as important players in signaling pathways that often exist in parallel with the UPS. Deubiquitinating enzymes (DUBs), responsible for reversing the ubiquitination reaction by removing covalently attached ubiquitin molecules from substrates or polyubiquitinated chains, have recently exploded onto the ubiquitin field as key regulators of both the UPS and of the nonproteolytic functions of ubiquitination. Thus, DUBs exert profound influence on many cellular pathways, including one of the best-studied biological processes involving DNA repair and damage response in mammalian cells.There are approximately 95 DUBs encoded by the human genome, which fall into one of the five subclasses: ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), Machado-Joseph domain-containing proteins (MJDs), Otubain domain-containing proteases (OTUs), and JAMM (JAB1/MPN/ Mov34) proteases (1, 2). Ubiquitin has seven internal lysine residues (Lys6,, each providing sites for the generation of an isopeptide bond with the carboxy terminus of another ubiquitin to form ubiquitin polymers, otherwise known as polyubiquitination. Linear ubiquitin chains can also be generated when the amino-terminal methionine (Met) of ubiquitin (Met1) forms a peptide bond with the carboxy-terminal glycine (Gly) of ubiquitin. As different types of polyubiquitin polymers adopt different conformations (3), it is not surprising that many DUBs show some degree of specificity toward differentially linked polyubiquitination, each of which results in a different physi...

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“…• double stranded DNA molecule [61][62][63]. Downstream proteins have an important role in this repair mechanism, connecting the FA-pathway with DSB repair [48,49].…”

Section: Citation: Selenti N Kattamis a Kanavakis E Kitsiou S Mavmentioning

confidence: 99%

Genetic Diagnosis of Fanconi Anemia

Selenti¹

2015

HBTD

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FANCD2 and CtIP Cooperate to Repair DNA Interstrand Crosslinks

Cited by 77 publications

References 45 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

Role of Deubiquitinating Enzymes in DNA Repair

Genetic Diagnosis of Fanconi Anemia

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