Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein

Motnenko, Anna; Liang, Chih-Chao; Yang, Di; Martínez, David López; Yoshikawa, Yasunaga; Zhan, Bao; Ward, Katherine E.; Tian, Jiayang; Haas, Wilhelm; Spingardi, Paolo; Kessler, Benedikt M.; Kriaucionis, Skirmantas; Gygi, Steven P.; Cohn, Martin A.

doi:10.1371/journal.pgen.1007643

Cited by 21 publications

(20 citation statements)

References 38 publications

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“…Interstrand crosslinks (ICLs), generated either by natural or synthetic compounds, are mostly resolved via the Fanconi Anemia (FA) pathway [ 14 ]. An increasing body of evidence suggests that ICLs are recognized by dedicated proteins, such as ubiquitin-like containing plant homeodomain, RING finger domains 1 (UHRF1) and UHRF2 that interact and facilitate the recruitment and retention of Fanconi anemia group D2 (FANCD2) protein at the ICL site [ 15 ]. This event is central to the function of the FA pathway, and FANCD2 posttranslational modifications are essential for proper regulation of this DNA repair pathway and subsequent resolution of ICLs [ 14 ].…”

Section: The Dna Damage Response Is Activated Upon Sensing Of Dna mentioning

confidence: 99%

DNA Damage: From Threat to Treatment

Carusillo

Mussolino

2020

Cells

152

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DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.

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Section: The Dna Damage Response Is Activated Upon Sensing Of Dna mentioning

confidence: 99%

DNA Damage: From Threat to Treatment

Carusillo

Mussolino

2020

Cells

152

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“…ICLs are repaired by the Fanconi anemia (FA) pathway during S phase when an X-shaped DNA structure is generated around the lesion via replication fork convergence or single-fork traverse of the ICL ( Huang et al, 2013 ; Zhang et al, 2015 ). ICL repair via the FA pathway is initiated upon lesion recognition of the ICL by the UHRF1 and UHRF2 proteins ( Motnenko et al, 2018 ) and the FANCM-MHF1-MHF2-FAAP24 complex, which recruit the FANCI-FANCD2 (FANCI-D2) heterodimer and the FA core complex to chromatin, respectively. The FA core complex is an E3 ubiquitin ligase that monoubiquitylates FANCI-D2 to facilitate recruitment of SLX4/FANCP and subsequently the association of DNA endonucleases MUS81, SLX1, FAN1, and XPF/ERCC4/FANCQ.…”

Section: Introductionmentioning

confidence: 99%

The ZGRF1 Helicase Promotes Recombinational Repair of Replication-Blocking DNA Damage in Human Cells

et al. 2020

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SUMMARY Replication-blocking DNA lesions are particularly toxic to proliferating cells because they can lead to chromosome mis-segregation if not repaired prior to mitosis. In this study, we report that ZGRF1 null cells accumulate chromosome aberrations following replication perturbation and show sensitivity to two potent replication-blocking anticancer drugs: mitomycin C and camptothecin. Moreover, ZGRF1 null cells are defective in catalyzing DNA damage-induced sister chromatid exchange despite accumulating excessive FANCD2, RAD51, and γ-H2AX foci upon induction of interstrand DNA crosslinks. Consistent with a direct role in promoting recombinational DNA repair, we show that ZGRF1 is a 5′-to-3′ helicase that catalyzes D-loop dissociation and Holliday junction branch migration. Moreover, ZGRF1 physically interacts with RAD51 and stimulates strand exchange catalyzed by RAD51-RAD54. On the basis of these data, we propose that ZGRF1 promotes repair of replication-blocking DNA lesions through stimulation of homologous recombination.

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“…Residual recruitment of the FANCD2/FANCI complex was observed upon depletion of WRNIP1, suggesting the presence of alternative mechanisms to support recruitment in the absence of WRNIP1. Perhaps the ICL sensor proteins UHRF1 and UHRF2 provide this activity ( Liang et al., 2015 ; Motnenko et al., 2018 ; Tian et al., 2015 ).…”

Section: Discussionmentioning

confidence: 99%

WRNIP1 Is Recruited to DNA Interstrand Crosslinks and Promotes Repair

et al. 2020

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Summary The Fanconi anemia (FA) pathway repairs DNA interstrand crosslinks (ICLs). Many FA proteins are recruited to ICLs in a timely fashion so that coordinated repair can occur. However, the mechanism of this process is poorly understood. Here, we report the purification of a FANCD2-containing protein complex with multiple subunits, including WRNIP1. Using live-cell imaging, we show that WRNIP1 is recruited to ICLs quickly after their appearance, promoting repair. The observed recruitment facilitates subsequent recruitment of the FANCD2/FANCI complex. Depletion of WRNIP1 sensitizes cells to ICL-forming drugs. We find that ubiquitination of WRNIP1 and the activity of its UBZ domain are required to facilitate recruitment of FANCD2/FANCI and promote repair. Altogether, we describe a mechanism by which WRNIP1 is recruited rapidly to ICLs, resulting in chromatin loading of the FANCD2/FANCI complex in an unusual process entailing ubiquitination of WRNIP1 and the activity of its integral UBZ domain.

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Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein

Cited by 21 publications

References 38 publications

DNA Damage: From Threat to Treatment

DNA Damage: From Threat to Treatment

The ZGRF1 Helicase Promotes Recombinational Repair of Replication-Blocking DNA Damage in Human Cells

WRNIP1 Is Recruited to DNA Interstrand Crosslinks and Promotes Repair

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