WRNIP1 Is Recruited to DNA Interstrand Crosslinks and Promotes Repair

Anna Socha,Di Yang,Alicja Bulsiewicz,Kelvin Yaprianto,Marian Kupculak,Chih-Chao Liang,Andreas Hadjicharalambous,Ronghu Wu,Steven P Gygi,Martin A Cohn

doi:10.1016/j.celrep.2020.107850

Anna Socha, Di Yang + Show 8 more

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https://doi.org/10.1016/j.celrep.2020.107850

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Journal: Cell Reports	Publication Date: Jul 1, 2020
Citations: 22	License type: cc-by

Affiliation: University of Oxford, Harvard University

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SummaryThe 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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Crosslinks holding the Watson-Crick strands of DNA together are highly toxic to cells
If WRNIP1 is recruited to interstrand crosslinks (ICLs) before FANCD2, recruitment of WRNIP1 may affect the subsequent recruitment of FANCD2
We observed no change in the recruitment of WRNIP1 in the absence of FANCD2 (Figure S4C). These data show that WRNIP1 is recruited to ICLs and that this recruitment facilitates the recruitment of the FANCD2/FANCI complex, potentially via a direct protein-protein interaction between the two proteins

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Crosslinks holding the Watson-Crick strands of DNA together are highly toxic to cells. One of the most studied pathways repairing this type of DNA damage in humans is the Fanconi anemia (FA) DNA repair pathway. FA primarily presents as a bone marrow failure disease, it has been associated with several other clinical manifestations, such as immune deficiency (Fagerlie and Bagby, 2006), endocrine dysfunction, osteoporosis, and cancer (Giri et al, 2007). The molecular basis for the phenotype in patients is mutation of any of the 22 FA genes associated with DNA crosslink repair, it remains a subject of discussion as to whether all clinical manifestations of FA stem directly from impaired DNA damage repair or from other not fully investigated causes (Niraj et al, 2019). Not all FA genes have been identified, and the mechanism of repair is not fully understood (Lopez-Martinez et al, 2016)

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