| Structural highlights
Function
[FAP20_HUMAN] Component of the Fanconi anemia (FA) complex required to recruit the FA complex to DNA interstrand cross-links (ICLs) and promote ICLs repair. Following DNA damage recognizes and binds 'Lys-63'-linked ubiquitin generated by RNF8 at ICLs and recruits other components of the FA complex. Promotes translesion synthesis via interaction with REV1.[1] [2] [3] [4]
Publication Abstract from PubMed
FAAP20 is an integral component of the Fanconi anemia core complex that mediates the repair of DNA interstrand crosslinks. The ubiquitin-binding capacity of the FAAP20 UBZ is required for recruitment of the Fanconi anemia complex to interstrand DNA crosslink sites and for interaction with the translesion synthesis machinery. Although the UBZ-ubiquitin interaction is thought to be exclusively encapsulated within the betabetaalpha module of UBZ, we show that the FAAP20-ubiquitin interaction extends beyond such a canonical zinc-finger motif. Instead, ubiquitin binding by FAAP20 is accompanied by transforming a disordered tail C-terminal to the UBZ of FAAP20 into a rigid, extended beta-loop that latches onto the complex interface of the FAAP20 UBZ and ubiquitin, with the invariant C-terminal tryptophan emanating toward I44Ub for enhanced binding specificity and affinity. Substitution of the C-terminal tryptophan with alanine in FAAP20 not only abolishes FAAP20-ubiquitin binding in vitro, but also causes profound cellular hypersensitivity to DNA interstrand crosslink lesions in vivo, highlighting the indispensable role of the C-terminal tail of FAAP20, beyond the compact zinc finger module, toward ubiquitin recognition and Fanconi anemia complex-mediated DNA interstrand crosslink repair.
Ubiquitin recognition by FAAP20 expands the complex interface beyond the canonical UBZ domain.,Wojtaszek JL, Wang S, Kim H, Wu Q, D'Andrea AD, Zhou P Nucleic Acids Res. 2014 Nov 20. pii: gku1153. PMID:25414354[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kim H, Yang K, Dejsuphong D, D'Andrea AD. Regulation of Rev1 by the Fanconi anemia core complex. Nat Struct Mol Biol. 2012 Jan 22;19(2):164-70. doi: 10.1038/nsmb.2222. PMID:22266823 doi:10.1038/nsmb.2222
- ↑ Ali AM, Pradhan A, Singh TR, Du C, Li J, Wahengbam K, Grassman E, Auerbach AD, Pang Q, Meetei AR. FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway. Blood. 2012 Apr 5;119(14):3285-94. doi: 10.1182/blood-2011-10-385963. Epub 2012, Feb 17. PMID:22343915 doi:http://dx.doi.org/10.1182/blood-2011-10-385963
- ↑ Leung JW, Wang Y, Fong KW, Huen MS, Li L, Chen J. Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4491-6. doi:, 10.1073/pnas.1118720109. Epub 2012 Mar 6. PMID:22396592 doi:http://dx.doi.org/10.1073/pnas.1118720109
- ↑ Yan Z, Guo R, Paramasivam M, Shen W, Ling C, Fox D 3rd, Wang Y, Oostra AB, Kuehl J, Lee DY, Takata M, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Li L, Seidman MM, Wang W. A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network. Mol Cell. 2012 Jul 13;47(1):61-75. doi: 10.1016/j.molcel.2012.05.026. Epub 2012, Jun 14. PMID:22705371 doi:10.1016/j.molcel.2012.05.026
- ↑ Wojtaszek JL, Wang S, Kim H, Wu Q, D'Andrea AD, Zhou P. Ubiquitin recognition by FAAP20 expands the complex interface beyond the canonical UBZ domain. Nucleic Acids Res. 2014 Nov 20. pii: gku1153. PMID:25414354 doi:http://dx.doi.org/10.1093/nar/gku1153
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