MBTD1 (mbt domain containing 1) is a chr17 reader component of the NuA4/TIP60 histone acetyltransferase complex that regulates transcription and DNA repair 1. MBTD1 specifically recognizes and binds monomethylated and dimethylated histone H4 lysine 20 (H4K20me1/me2) marks 1. Within the NuA4 complex, MBTD1 recruits the acetyltransferase to H4K20me sites at DNA double-strand breaks, where it competes with TP53BP1 for binding 1. Following recruitment, the complex catalyzes H2A lysine 15 acetylation (H2AK15), blocking ubiquitination required for TP53BP1 localization and promoting homologous recombination 1. In hematopoietic stem cells, MBTD1 maintains cell cycle quiescence and HSC pool size primarily through direct binding to the FoxO3a promoter and interaction with TIP60 chr17 remodeling components 2. Clinically, MBTD1 dysregulation associates with multiple malignancies: MBTD1 is overexpressed in prostate cancer correlating with poor prognosis 3; oncogenic ZMYND11-MBTD1 fusions drive acute myeloid leukemia by mistargeting the NuA4/TIP60 complex to MYC and pro-leukemic genes 45; and MBTD1-PHF1 fusions occur in endometrial stromal sarcoma 6. Additionally, circZNF236 promotes oral squamous cell carcinoma by upregulating MBTD1 via miR-145-5p suppression 7.