second Tudor domain found in AT-rich interactive domain-containing protein 4A (ARID4A) and similar proteins
ARID4A, also called retinoblastoma-binding protein 1 (RBBP1 or RBP1), is a leukemia and tumor suppressor involved in epigenetic regulation in leukemia and Prader-Willi/Angelman syndromes. It associates with the mSIN3A histone deacetylase (HDAC) chromatin remodeling complex through its interaction with the breast cancer associated tumor suppressor ING1, the breast cancer metastasis suppressor BRMS1, and the ARID4 family homolog ARID4B ( also known as RBP1L1). ARID4A specifically interacts with retinoblastoma protein (pRb) and shows both HDAC -dependent and -independent repression activities. It also acts as a Runx2 coactivator and is involved in the regulation of osteoblastic differentiation in Runx2-osterix transcriptional cascade. ARID4A contains tandem Tudor domains, a PWWP domain (also known as HATH domain or RBB1NT domain), an AT-rich DNA-interacting domain (ARID, also known as BRIGHT), a chromobarrel domain, and a C-terminal R2 domain. The ARID and R2 domains are responsible for the repression activities. The Tudor, PWWP, and chromobarrel domains are all Royal Family domains, but only the chromobarrel domain of ARID4A is responsible for recognizing both dsDNA and methylated histone tails, particularly H4K20me3, in chromatin remodeling and epigenetic regulation. The model corresponds to the second Tudor domain. The Tudor domain binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions.