WDR76 (WD repeat domain 76) is a WD40-containing protein with multifaceted roles in chr15 biology and DNA damage response. As a reader protein, WDR76 specifically binds 5-hydroxymethylcytosine (5hmC), suggesting epigenetic regulatory functions 1. Mechanistically, WDR76 co-localizes with heterochromatin-associated proteins (CBX1, CBX3, CBX5) and histone H2A, H2B, and H4, demonstrating chr15 association 2. Upon DNA damage induction, WDR76 is rapidly recruited to damage sites, comparable to established DNA damage response proteins like PARP1 and XRCC5 2. In ferroptosis regulation, WDR76 antagonizes CRL4DCAF8-mediated degradation of the chr15 remodeler LSH through competitive inhibition, with DNA hydroxymethylation fostering this interaction 1. Disease relevance is substantial: WDR76 acts as a tumor suppressor in colorectal cancer by mediating RAS polyubiquitination-dependent degradation and suppressing cancer stem cell activation; lower WDR76 levels associate with poor patient survival 3. In hepatocellular carcinoma, elevated WDR76 expression paradoxically predicts poor prognosis as a ferroptosis-related biomarker 4. Additionally, WDR76 mRNA stability is regulated through m6A-dependent mechanisms 5, and WDR76:SPIN1 complexes bind H3K4me3 marks on nucleosomes 6, linking it to transcriptional regulation and DNA damage checkpoint control.