Specifically deubiquitinates 'Lys-14' (H2AK13Ub) and 'Lys-16'(H2AK15Ub) of histone H2A regulating the DNA damage response at double-strand breaks (DSBs) (PubMed:27083998). USP51 is recruited to chromatin after DNA damage and regulates the dynamic assembly/disassembly of TP53BP1 and BRCA1. Exhibits also activity for 'Lys-27' or 'Lys-63'-linked di-ubiquitin (PubMed:27083998). Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). Interacts with H2A (PubMed:27083998). Upon DNA damage, chromatin-bound USP51 disassociates from chromatin immediately following DNA damage and reassociates with chromatin following DNA repair. Expressed in prostate, brain, lung, aorta and kidney. Belongs to the peptidase C19 family. Contaminating sequence. Potential poly-A sequence.