Mechanism of RAD51-Dependent DNA Interstrand Cross-Link Repair

Long, David T.; Räschle, Markus; Joukov, Vladimir; Walter, Johannes C.

doi:10.1126/science.1204258

Cited by 213 publications

(243 citation statements)

References 17 publications

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“…Therefore it is tempting to speculate that UAF1 may serve to coordinate the interaction with the FANCD2-FANCI complex, ELG1-PCNA, and RAD51AP1, during the repair of ICL or during the replication stresses. As RAD51-driven HR reaction is necessary during the ICL repair, 41 the functional connection between the FA pathway and HR machineries is further supported by our work.…”

Section: Discussionsupporting

confidence: 64%

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: Discussionsupporting

confidence: 64%

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

et al. 2016

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“…The RAD51 recombinase plays a key role in the HR-mediated repair of DSBs, DSGs, and ICLs (15)(16)(17). The RAD51 paralog RAD51C is known to regulate HR in coordination with other RAD51 paralogs as follows: RAD51B, RAD51D, XRCC2, and XRCC3 (18).…”

mentioning

confidence: 99%

Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

Somyajit

Subramanya

Nagaraju

2012

Journal of Biological Chemistry

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Background: RAD51C plays a key role in recombinational repair and genome stability. Results: RAD51C deficiency leads to repair as well as a signaling defect in response to interstrand cross-links and double strand breaks. Conclusion: RAD51C is critical for Fanconi anemia pathway of ICL repair and intra-S-phase checkpoint. Significance: This study identifies distinct roles of RAD51C in repair and signaling and as a tumor suppressor.

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“…This mechanism requires the convergence of two replication forks at an ICL during DNA replication (Zhang et al , 2015). Both forks initially stall 20–40 nucleotides from the crosslink followed by CMG helicase unloading allowing one fork to approach to within 1 nucleotide of the crosslink (Räschle et al , 2008; Fu et al , 2011; Long et al , 2011). Dual incisions on either side of the ICL then unhook the lesion from one of the strands.…”

Section: Introductionmentioning

confidence: 99%

“…After unhooking, a nucleotide is inserted across from the adducted base, followed by strand extension by REV1 and polymerase ζ, consisting of REV7 (FANCV) and REV3 (Räschle et al , 2008; Budzowska et al , 2015; Mamrak et al , 2016). This strand now acts as a template for repair of the opposite strand by HR (Long et al , 2011), leading to fully repaired products.…”

Section: Introductionmentioning

confidence: 99%

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

et al. 2017

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XPF‐ERCC1 is a structure‐specific endonuclease pivotal for several DNA repair pathways and, when mutated, can cause multiple diseases. Although the disease‐specific mutations are thought to affect different DNA repair pathways, the molecular basis for this is unknown. Here we examine the function of XPF‐ERCC1 in DNA interstrand crosslink (ICL) repair. We used Xenopus egg extracts to measure both ICL and nucleotide excision repair, and we identified mutations that are specifically defective in ICL repair. One of these separation‐of‐function mutations resides in the helicase‐like domain of XPF and disrupts binding to SLX4 and recruitment to the ICL. A small deletion in the same domain supports recruitment of XPF to the ICL, but inhibited the unhooking incisions most likely by disrupting a second, transient interaction with SLX4. Finally, mutation of residues in the nuclease domain did not affect localization of XPF‐ERCC1 to the ICL but did prevent incisions on the ICL substrate. Our data support a model in which the ICL repair‐specific function of XPF‐ERCC1 is dependent on recruitment, positioning and substrate recognition.

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Mechanism of RAD51-Dependent DNA Interstrand Cross-Link Repair

Cited by 213 publications

References 17 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

Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

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