| Structural highlights
Disease
RFWD3_HUMAN Fanconi anemia, complementation group W (FANCW): A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair (PubMed:28575657). The disease is caused by mutations affecting the gene represented in this entry.[1]
Function
RFWD3_HUMAN E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658). Plays a key role in RPA-mediated DNA damage signaling and repair (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658). Acts by mediating ubiquitination of the RPA complex (RPA1, RPA2 and RPA3 subunits) and RAD51 at stalled replication forks, leading to remove them from DNA damage sites and promote homologous recombination (PubMed:26474068, PubMed:28575657, PubMed:28575658). Also mediates the ubiquitination of p53/TP53 in the late response to DNA damage, and acts as a positive regulator of p53/TP53 stability, thereby regulating the G1/S DNA damage checkpoint (PubMed:20173098). May act by catalyzing the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:20173098). In response to ionizing radiation, interacts with MDM2 and enhances p53/TP53 ubiquitination, possibly by restricting MDM2 from extending polyubiquitin chains on ubiquitinated p53/TP53 (PubMed:20173098).[2] [3] [4] [5] [6] [7]
See Also
References
- ↑ Feeney L, Munoz IM, Lachaud C, Toth R, Appleton PL, Schindler D, Rouse J. RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health. Mol Cell. 2017 Jun 1;66(5):610-621.e4. doi: 10.1016/j.molcel.2017.04.021. PMID:28575657 doi:http://dx.doi.org/10.1016/j.molcel.2017.04.021
- ↑ Fu X, Yucer N, Liu S, Li M, Yi P, Mu JJ, Yang T, Chu J, Jung SY, O'Malley BW, Gu W, Qin J, Wang Y. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4579-84. doi:, 10.1073/pnas.0912094107. Epub 2010 Feb 19. PMID:20173098 doi:10.1073/pnas.0912094107
- ↑ Gong Z, Chen J. E3 ligase RFWD3 participates in replication checkpoint control. J Biol Chem. 2011 Jun 24;286(25):22308-13. doi: 10.1074/jbc.M111.222869. Epub, 2011 Apr 18. PMID:21504906 doi:http://dx.doi.org/10.1074/jbc.M111.222869
- ↑ Liu S, Chu J, Yucer N, Leng M, Wang SY, Chen BP, Hittelman WN, Wang Y. RING finger and WD repeat domain 3 (RFWD3) associates with replication protein A (RPA) and facilitates RPA-mediated DNA damage response. J Biol Chem. 2011 Jun 24;286(25):22314-22. doi: 10.1074/jbc.M111.222802. Epub, 2011 May 9. PMID:21558276 doi:http://dx.doi.org/10.1074/jbc.M111.222802
- ↑ Elia AE, Wang DC, Willis NA, Boardman AP, Hajdu I, Adeyemi RO, Lowry E, Gygi SP, Scully R, Elledge SJ. RFWD3-Dependent Ubiquitination of RPA Regulates Repair at Stalled Replication Forks. Mol Cell. 2015 Oct 15;60(2):280-93. doi: 10.1016/j.molcel.2015.09.011. PMID:26474068 doi:http://dx.doi.org/10.1016/j.molcel.2015.09.011
- ↑ Feeney L, Munoz IM, Lachaud C, Toth R, Appleton PL, Schindler D, Rouse J. RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health. Mol Cell. 2017 Jun 1;66(5):610-621.e4. doi: 10.1016/j.molcel.2017.04.021. PMID:28575657 doi:http://dx.doi.org/10.1016/j.molcel.2017.04.021
- ↑ Inano S, Sato K, Katsuki Y, Kobayashi W, Tanaka H, Nakajima K, Nakada S, Miyoshi H, Knies K, Takaori-Kondo A, Schindler D, Ishiai M, Kurumizaka H, Takata M. RFWD3-Mediated Ubiquitination Promotes Timely Removal of Both RPA and RAD51 from DNA Damage Sites to Facilitate Homologous Recombination. Mol Cell. 2017 Jun 1;66(5):622-634.e8. doi: 10.1016/j.molcel.2017.04.022. PMID:28575658 doi:http://dx.doi.org/10.1016/j.molcel.2017.04.022
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