Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4

Kim, Yonghwan; Spitz, Gabriella S.; Veturi, Uma; Lach, Francis P.; Auerbach, Arleen D.; Smogorzewska, Agata

doi:10.1182/blood-2012-07-441212

Cited by 149 publications

(237 citation statements)

References 47 publications

(83 reference statements)

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“…We found that the XE G314E and XE ΔNSGW mutants were both able to interact normally with full‐length SLX4 (Figs 6B and EV5D). This is consistent with previous reports showing that the BTB domain is not essential for SLX4 and XPF interaction (Kim et al , 2013; Guervilly et al , 2015). One explanation for these observations is that this interaction is transient and can only be observed in the absence of the major interaction site involving the MLR domain.…”

Section: Resultssupporting

confidence: 94%

“…In contrast to wild‐type SLX4, the ΔMLR mutant was not able to bind XPF from Xenopus egg extract (Fig 6D). This shows that the MLR domain of SLX4 acts as the major interaction site with XPF, which is in line with previous reports in human cells (Kim et al , 2013). Based on our data, this domain most likely interacts with leucine 219 of XPF.…”

Section: Resultssupporting

confidence: 93%

“…We and others have shown that the MLR domain of SLX4 is essential for the interaction with XPF (Fig 6 and Kim et al , 2013), but it was not known which site on XPF was involved in this interaction. We now show that the XPF leucine 219 to arginine mutant is defective in binding to SLX4 indicating this is the site that interacts with the MLR domain.…”

Section: Discussionmentioning

confidence: 89%

“…This yeast two‐hybrid assay was performed with C‐terminal deletion mutants of SLX4 and the interaction with XPF was pinpointed to the BTB domain. However, these mutants lacked the MLR domain which has also been implicated in the interaction with XPF (Kim et al , 2013). In our hands, the equivalent mutation in xl XPF, G314E, did not abrogate ICL repair or recruitment.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 94%

Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…The N-terminal segment of SLX4/FANCP harbors ubiquitin zinc finger (UBZ) domains, suggesting that SLX4 is recruited to DNA damage via interaction with ubiquitinated proteins involved in the DNA damage response (DDR). SLX4 recruitment in chicken DT-40 cells may depend on FANCD2 monoubiquitination but with uncertain relevance to mammals [50]. SLX4 serves as a scaffold that organizes specific nucleases for transport to DNA lesions and regulates nuclease activity [50,51].…”

Section: Fa Genes (Fanca B C D1 D2 E F G I J L N P Q) Fmentioning

confidence: 99%