{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DCAF5 is a member of the “DDB1 and CUL4‐associated factor” family that is believed to function as a substrate receptor within the CRL4 (Cullin‐4–RING) E3 ubiquitin ligase complexes. Although its biochemical activity has not been detailed in every study, one report identified DCAF5 among a cluster of 19 genes within a recurrent deletion at chromosome band 14q24.1–q24.3; haploinsufficiency of these genes—including DCAF5—was implicated in neurodevelopmental abnormalities, congenital heart defects, and dysmorphic features, suggesting that normal DCAF5 expression may be required to maintain proper developmental signaling and cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In parallel, other studies have described how methyl-binding proteins, such as L3MBTL3, recognize specific lysine methylation marks on target proteins and recruit novel CRL4 complexes to trigger ubiquitination and proteolysis. For instance, methylation-dependent degradation of epigenetic regulators (e.g., DNMT1 and SOX2) was shown to occur upon recruitment of CRL4 complexes by methyl readers, highlighting a general mechanism by which substrate receptors control protein turnover."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Structural investigations of the CRL4 machinery further indicate that cellular substrate-recruiting factors (the DCAFs) share common motifs with viral proteins that hijack these complexes, underscoring the critical role of appropriate substrate recognition for proteostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Although DCAF5 was not directly functionally characterized in these studies, its inclusion in a deleted genomic interval associated with developmental defects strongly supports its role in targeting proteins for regulated degradation via a CRL4-dependent pathway. Disruption of this degradation machinery, potentially through DCAF5 insufficiency, may result in the accumulation or inappropriate depletion of proteins that govern cell cycle progression, epigenetic regulation, and developmental signaling, thereby contributing to the pathology observed in affected individuals.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Barbara Oehl-Jaschkowitz, Olivier M Vanakker, Anne De Paepe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deletions in 14q24.1q24.3 are associated with congenital heart defects, brachydactyly, and mild intellectual disability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.36321"}], "href": "https://doi.org/10.1002/ajmg.a.36321"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24357125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24357125"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Feng Leng, Jiekai Yu, Chunxiao Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "DCAF5"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " ubiquitin ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-04019-9"}], "href": "https://doi.org/10.1038/s41467-018-04019-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29691401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29691401"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Chunxiao Zhang, Feng Leng, Lovely Saxena, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proteolysis of methylated SOX2 protein is regulated by L3MBTL3 and CRL4"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "DCAF5"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " ubiquitin ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA118.005336"}], "href": "https://doi.org/10.1074/jbc.RA118.005336"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30442713"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30442713"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ti Li, Eva I Robert, Pieter C van Breugel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb.1719"}], "href": "https://doi.org/10.1038/nsmb.1719"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19966799"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19966799"}]}]}]}